Feline Dermatology (VetBooks.ir)

VetBooks.ir Chiara Noli · Silvia Colombo Editors Feline Dermatology VetBooks.ir Feline Dermatology VetBooks.ir Chiara Noli • Silvia Colombo Editors Feline Dermatology VetBooks.ir Editors Chiara Noli Servizi Dermatologici Veterinari Peveragno Italy Silvia Colombo Servizi Dermatologici Veterinari Legnano Italy ISBN 978-3-030-29835-7 ISBN 978-3-030-29836-4 https://doi.org/10.1007/978-3-030-29836-4 (eBook) © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland VetBooks.ir Foreword for Feline Dermatology In 1980, Danny Scott (James Law Professor Emeritus, Section of Dermatology at Cornell University, New York, USA) published a monograph in the Journal of the American Animal Hospital Association, entitled Feline dermatology 1900-1978: A Monograph. This was the first comprehensive survey of skin diseases in the domestic cat; there had previously been other small descriptive articles and booklets. This was the first attempt to review all that was known at the time in veterinary science. Since 1980, cats and their skin conditions have always been part of standard textbooks of veterinary dermatology and veterinary science; Danny Scott published several more monographs. In 1999, Merial published a book entitled A Practical Guide to Feline Dermatology, devoted to cats and compiled by a multinational large author group. While cats make popular pets, they have always been challenging to examine, to study, to investigate, and to treat. For example, they don’t readily take to diet trials or accept long courses of oral medications; furthermore, trying to identify clinically significant allergens remains something of a dark art. They have always been remarkably independent creatures, and we never really “own them” as a pet. We remain enthralled with them in part because of their aloof persona as well as their engaging personalities. In some respects, the level of understanding of their skin diseases has always lagged behind other domestic animals, especially the dog (with the old adage that a cat is not a small dog). Some 20 years after the publication of the book A Practical Guide to Feline Dermatology, we have this new book Feline Dermatology. The editors have emulated the guide and assembled a large international community of authors who share their experience and expertise in studying and caring for cats and their skin diseases. The book comprises three sections. The first section introduces the structure and function of the skin – the fundamental building blocks that help students and veterinarians to understand the pathogenesis of skin diseases. It is nice to see a chapter on coat color genetics – a topic often left for other publications and not included with clinical dermatology textbooks. The next section provides a series of chapters that discuss the various clinical presentations of skin diseases in cats with, for example, an approach to the skin diseases associated with alopecia and so on. Given that cats can present with different cutaneous presentations to the same underlying aetiology, this section is followed by the third section that covers a large array of skin diseases organized by aetiology. v VetBooks.ir vi Foreword for Feline Dermatology The coverage is comprehensive and so there are chapters that will be useful for students, veterinarians in general practice, residents in training programs, including dermatology, for veterinarians working in referral centers, and maybe even some cat owners. There are many illustrations and clinical images that befit the discipline of veterinary dermatology, which is so reliant on visual representation to appreciate and understand clinical lesions and the cutaneous reaction patterns that may be presented. The editors are to be congratulated on assembling such an array of chapters and topics, demonstrating that our knowledge and understanding of feline dermatology has come a long way since the first monographs. This is the first major book on feline dermatology in many years and should prove to be a useful reference text for veterinarians for many years to come. Veterinary clinicians may gain a lot of knowledge from the internet but printed books remain popular with publishers and veterinarians. This is one book you ought to have on your shelf. Aiden P. Foster Bristol Veterinary School University of Bristol Langford, UK VetBooks.ir Preface The world of veterinary dermatology is growing rapidly year after year, as is true for our knowledge of all animal diseases. The cat is currently receiving great attention in veterinary medicine: many feline-specific textbooks have been published in recent years; we have now feline-specific scientific journals, and “feline specialists” are more and more numerous. Being veterinary dermatologists with a particular interest in cats, we felt the need for a feline dermatology textbook. Our aim was to dedicate the appropriate attention to the cat’s skin and its diseases, which are often peculiar and totally different from the counterparts described in dogs. A long time has passed by since two previous feline dermatology books A Practical Guide to Feline Dermatology by Eric Guaguère and Pascal Prélaud and Skin Diseases of the Cat by Sue Paterson, which were both published in 1999. After 20 years, it was time for a new feline dermatology textbook and here it is! This book will hopefully serve both as an essential practical guide for the busy practitioner, to quickly and surely tackle cats with dermatological conditions, and a current and complete reference tool for the feline veterinarian and the veterinary dermatologist. The most important feline skin diseases such as dermatophytosis and allergic diseases are described in dedicated chapters. We decided to select different authors for the majority of the chapters, in order to provide readers with the best possible review for each subject, written by experts in their specific fields. Each chapter is greatly enriched with many beautiful colour pictures, which are indispensable to properly describe a skin disease. We are very grateful to Springer Nature and all their team for supporting our project with enthusiasm. Last but not least, we want to say a huge thanks to all the authors who contributed to this book. Dedicated to: Emma, Ada, Luca and all the cats of our lives. Peveragno, Italy Legnano, Italy Chiara Noli Silvia Colombo vii VetBooks.ir Contents Part I Introductory Chapters tructure and Function of the Skin�� 3 S Keith E. Linder oat Color Genetics�� 23 C Maria Cristina Crosta pproach to the Feline Patient: General and Dermatological A Examination�� 67 Andrew H. Sparkes and Chiara Noli Part II Problem Oriented Approach to…: Alopecia�� 95 Silvia Colombo Papules, Pustules, Furuncles and Crusts �� 109 Silvia Colombo laques, Nodules and Eosinophilic Granuloma Complex Lesions�� 123 P Silvia Colombo and Alessandra Fondati xcoriations, Erosions and Ulcers�� 137 E Silvia Colombo Scaling �� 149 Silvia Colombo Pruritus �� 161 Silvia Colombo Otitis�� 175 Tim Nuttall ix x Contents VetBooks.ir Part III Feline Skin Diseases by Etiology Bacterial Diseases�� 213 Linda Jean Vogelnest Mycobacterial Diseases�� 251 Carolyn O’Brien Dermatophytosis�� 265 Karen A. Moriello eep Fungal Diseases�� 297 D Julie D. Lemetayer and Jane E. Sykes Sporothrichosis�� 329 Hock Siew Han alassezia �� 345 M Michelle L. Piccione and Karen A. Moriello Viral Diseases�� 359 John S. Munday and Sylvie Wilhelm Leishmaniosis �� 387 Maria Grazia Pennisi Ectoparasitic Diseases�� 405 Federico Leone and Hock Siew Han lea Biology, Allergy and Control�� 437 F Chiara Noli eline Atopic Syndrome: Epidemiology and Clinical Presentation�� 451 F Alison Diesel eline Atopic Syndrome: Diagnosis�� 465 F Ralf S. Mueller Feline Atopic Syndrome: Therapy�� 475 Chiara Noli Mosquito-byte Hypersensitivity�� 489 Ken Mason Autoimmune Diseases�� 495 Petra Bizikova I mmune Mediated Diseases�� 511 Frane Banovic VetBooks.ir Contents xi ormonal and Metabolic Diseases �� 531 H Vet Dominique Heripret and Hans S. Kooistra Genetic Diseases �� 547 Catherine Outerbridge Psychogenic Diseases �� 567 C. Siracusa and Gary Landsberg Neoplastic Diseases�� 583 David J. Argyle and Špela Bavčar Paraneoplastic Syndromes�� 613 Sonya V. Bettenay I diopathic Miscellaneous Diseases�� 627 Linda Jean Vogelnest and Philippa Ann Ravens VetBooks.ir Contributors David J. Argyle The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK Frane Banovic University of Georgia, College of Veterinary Medicine, Department of Small Animal Medicine and Surgery, Athens, GA, USA Špela Bavčar The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK Sonya V. Bettenay Tierdermatologie Deisenhofen, Deisenhofen, Germany Petra Bizikova North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA Silvia Colombo Servizi Dermatologici Veterinari, Legnano, Italy Maria Cristina Crosta Clinica Veterinaria Gran Sasso, Milan, Italy Alison Diesel College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA Alessandra Fondati Veterinaria Trastevere - Veterinaria Cetego, Roma, RM, Italy Clinica Veterinaria Colombo, Camaiore, LU, Italy Vet Dominique Heripret CHV Fregis, Arcueil, France CHV Pommery, Reims, France Hans S. Kooistra Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Gary Landsberg CanCog Technologies, Fergus, ON, Canada Julie D. Lemetayer Veterinary Medical Teaching Hospital, University of California, Davis, CA, USA Federico Leone Clinica Veterinaria Adriatica, Senigallia (Ancona), Italy Keith E. Linder College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA xiii VetBooks.ir xiv Contributors Ken Mason Specialist Veterinary Dermatologist, Animal Allergy & Dermatology Service, Slacks Creek, QLD, Australia Karen A. Moriello School of Veterinary Medicine, University of Wisconsin- Madison, Madison, WI, USA Ralf S. Mueller Centre for Clinical Veterinary Medicine, München, Germany John S. Munday Massey University, Palmerston North, New Zealand Chiara Noli Servizi Dermatologici Veterinari, Peveragno, Italy Tim Nuttall Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, UK Carolyn O’Brien Melbourne Cat Vets, Fitzroy, Victoria, Australia Catherine Outerbridge University of California, Davis, Davis, CA, USA Maria Grazia Pennisi Dipartimento di Scienze Veterinarie, Università di Messina, Messina, Italy Michelle L. Piccione School of Veterinary Medicine, University of Wisconsin- Madison, Madison, WI, USA Philippa Ann Ravens Small Animal Specialist Hospital, North Ryde, NSW, Australia Hock Siew Han The Animal Clinic, Singapore C. Siracusa Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA Andrew H. Sparkes Simply Feline Veterinary Consultancy, Shaftesbury, UK Jane E. Sykes Veterinary Medical Teaching Hospital, University of California, Davis, CA, USA Linda Jean Vogelnest University of Sydney, Sydney, NSW, Australia Small Animal Specialist Hospital, North Ryde, NSW, Australia Sylvie Wilhelm Vet Dermatology GmbH, Richterswil, Switzerland VetBooks.ir Part I Introductory Chapters VetBooks.ir Structure and Function of the Skin Keith E. Linder Abstract Knowledge of skin anatomy and function is fundamental for understanding the clinical manifestations and impacts of skin diseases. While true for any organ, this is especially true for the skin, because clinicians can see, touch, and otherwise interrogate the anatomy of this organ directly. Importantly, skin diseases result from deleterious agents or processes that disrupt specific anatomic components of the skin, and induce physiological responses that distort it, to create skin lesions. Recognition of skin lesion significance, and thus diseases, is based upon identifying alterations in normal skin anatomy, including the particular anatomical components that are targeted. Furthermore, the impacts of skin diseases and treatment choices are understood through knowledge of normal skin functions and the consequences of its dysfunction. This chapter reviews basic aspects of feline skin structure and function, with citations from the literature where available, and draws heavily on the comparative information available for humans and dogs. The Skin Organ The skin is organized into multiple, discrete, thin layers that are stacked to create a sheetlike organ that covers the entire body [1]. Starting externally, the epidermis is supported by the dermis and then by the panniculus, which connects via fascia to the underlying musculature or periosteum, for example, in the extremities (Fig. 1). Nerves and sensory nerve endings invest all three layers variably, whereas blood K. E. Linder (*) College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA e-mail: kelinder@ncsu.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_1 3 K. E. Linder VetBooks.ir 4 Fig. 1 Dorsal mid back, cat. The skin is organized into sheet-like tissue layers. The very thin epidermis (E) is on the surface and is supported below by the collagenous dermis (D). The panniculus is deepest and is composed of three parts, in areas of the body where all three are present. The panniculus adiposus (PA) is composed of lobules of adipose, and its most superficial part, the superficial adipose tissue, is shown here. The collagenous panniculus fibrosis (PF, superficial fascia) supports the panniculus carnosus (PC), which is composed of striated skeletal muscle. Adnexa are added into these layers, of which hair follicles (HF) are most visible at this magnification. 4X magnification. Hematoxylin and eosin vessels are found only in the dermis and panniculus. The skin adnexa (appendages) are “little organs” added into these three layers multifocally during development and include, for example, hair follicles, skin glands, and claws. All three skin layers are highly modified to create discrete anatomical structures like the planum nasale and footpads. The skin thickness, made of the dermis and epidermis together, varies by body region and is only generally 0.4–2.0 millimeters thick in the cat, being thicker on the dorsal body and proximal limbs and thinner on the ventral body, distal limbs, and ears [2]. These layers are the thickest on the footpads and planum nasale [2]. The panniculus varies greatly in thickness, being absent to >2 centimeters, depending on the degree of adiposity of the patient and the anatomical region of the body; it is generally thickest on the ventrum, especially in obese patients, thinner on the dorsum, and progressively thins to become mostly absent on the extremities. Structure and Function of the Skin 5 VetBooks.ir Epidermis The epidermis is remarkably thin (Fig. 2) and measures only 10–25 micrometers in truncal areas, but is thicker on footpads (Fig. 3) and planum nasale [2, 3]. In most body areas, the viable epidermis contains only three to five keratinocyte layers. The superficial nonviable epidermis, the stratum corneum, contains more numerous cell layers composed of very thin cells, called corneocytes, which are less than 1 micrometer thick (Fig. 2). Haired areas tend to have thinner epidermis than nonhaired areas. The epidermis is a stratified cornifying epithelium composed of keratinocytes (85%) arranged in four layers based on morphology: the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum (Fig. 2) [1]. Keratinocytes continually proliferate in the basal epidermal layer, then migrate, and differentiate to form the upper epidermal layers and finally shed (desquamate) from the skin surface. The epidermis also contains resident Langerhans cells, migrating T-lymphocytes, and uncommon neuroendocrine Merkel cells (<1%) [1]. Melanocytes are present in pigmented epidermis and are absent in areas of white spotting. In the cat, mast cells are rare in the epidermis but can move into the epidermis in greater numbers during inflammatory diseases such as allergic skin diseases. Nerves extend into the epidermis but blood vessels do not. Fig. 2 Face, cat. The epidermis is composed of four morphological layers: stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC). The deep stratum corneum, called the stratum compactum (arrowheads), is very thin and formed by compact orthokeratosis. The superficial stratum corneum, called the stratum dysjunctum (arrows), is expanded mostly by histology artifact into a basket weave pattern of orthokeratosis. The basement membrane zone (BMZ; location of the ultramicroscopic basement membrane) connects the epidermis to the dermis (D). Fibrocytes (F) and mast cells (MC) are in the dermis. 100X magnification. Hematoxylin and eosin K. E. Linder VetBooks.ir 6 Fig. 3 Carpal footpad, cat. Footpads (including digital pads) have a thick epidermis, with a robust stratum corneum (SC), and thick dermis (D). Hair follicles (HF) and sebaceous glands are absent in footpads but are present in haired skin at the footpad margin (left of the image). Footpad cushions (C) are discrete modifications of the panniculus and contain small lobules of adipose with robust fibrous septa. Eccrine glands (EG) are embedded in the cushion, and eccrine ducts (ED) exit directly through the dermis and epidermis to empty onto the footpad surface. 4X magnification. Hematoxylin and eosin The deepest epidermal layer, the stratum basale (stratum germinativum), contains epidermal stem cells with mitotic activity and continually supplies new keratinocytes to all epidermal layers (Fig. 2) [1, 4]. Basal layer keratinocytes are smaller and more cuboidal, with less cytoplasm, and attach the epidermis to its basement membrane and thus to the dermis. Moving up, the stratum spinosum is named for the spinous projections observed on keratinocyte membranes with paraffin section histology – an artifact of tissue processing that accentuates desmosomal attachments between cells. Spinous layer cells are larger due to more abundant cytoplasm, are polyhedral, and have more visible cytoplasmic keratin intermediate filaments. Next, the stratum granulosum is named for cytoplasmic, basophilic keratohyalin granules that are visible with hematoxylin and eosin (H&E) staining and store mostly proteins, like profilaggrin, needed for cornification [4]. Lamellar bodies, not visible with paraffin histology, form in this layer as well and deliver lipids, enzymes, and other key components to the extracellular surface during cornification [4]. The stratum corneum, the external most layer of the epidermis, forms by terminal differentiation called cornification, which creates nonviable corneocytes from the viable granular layer keratinocytes below [4]. During this process, keratinocytes loose most of their cytoplasmic water and organelles and flatten to become very thin (less than 1 micrometer) discoid cells with linear faceted (5–6) margins. The nucleus is also lost, and thus the cornification is orthokeratotic. On paraffin histology, the deep corneocytes are densely compacted into a discrete layer called the stratum compactum, and the superficial corneocytes are separated on their faces, VetBooks.ir Structure and Function of the Skin 7 because of processing artifact, in an open basket weave pattern in a layer called the stratum dysjunctum (Fig. 2) [5]. Corneocytes are continually shed from the body in a process called desquamation. In the stratum corneum, corneocytes are stacked into many layers, approximately 10 to 15 on the trunk and 50+ on the footpads and planum nasale, and are sealed by intercellular lipids [3]. Fewer corneocyte layers are present in haired, low friction areas and more are in high friction areas such as palmar and plantar footpad surfaces. On the trunk, corneocytes are stacked into uniform vertical columns, overlapping only slightly at their margins, whereas on the footpads, corneocyte stacking is nonuniform and cells overlap extensively and variably, creating greater cell-to-cell surface contact, which is thought to increase adhesion. Intercellular lipids, delivered by lamellar bodies, are highly organized into a stack of lipids called the lipid envelop, which seals the entire extracellular space and creates the most important barrier preventing external water loss from the skin.4 These lipids are composed of ceramides, cholesterol, and fatty acids. Certain lipids, like linoleic acid, are essential and are very important for lipid envelop formation and function. Corneocytes are continually shed from the skin surface by desquamation. Desquamation occurs because the normal physiochemical environment (pH, hydration, etc.) of outer stratum corneum promotes activation of numerous intercellular enzymes to cleave corneodesmosomes and degrade intercellular lipids, which allows corneocytes to separate away [4]. Clinically, a buildup of the stratum corneum on the skin surface, either due to increased production of corneocytes or altered desquamation, is called scaling. Partial loss of the epidermis leads to an erosion, which causes water loss from the skin surface. Eroded epidermis appears smooth and slightly moist due to the missing stratum corneum, which is responsible for normal epidermal surface architecture and barrier function. Eroded epidermis lacks hemorrhage as the epidermis does not contain blood vessels. In contrast, complete loss of the epidermis and the basement membrane is an ulcer, which appears moist to wet and granular (because of collagen exposure and recruited leukocytes and fibrin), and it often contains hemorrhage because of exposed dermal blood vessels. Epidermal Basement Membrane The epidermal basement membrane (basal lamina) is composed of numerous filamentous proteins and proteoglycans that bind together to form an ultrathin, mesh-like sheet that supports the basal cells and blankets the dermis [6]. Basal cells are structurally connected by hemidesmosomes to the basement membrane, which in turn is connected to the dermis by anchoring fibrils composed of collagen VII. Basement membrane zone is used to refer to this structure on light microscopic histology because it is too thin to be directly visualized (Fig. 2). Epidermal strength results from physical interconnections between cytoskeletal proteins, cellular adhesion complexes (desmosomes and hemidesmosomes), and the VetBooks.ir 8 K. E. Linder epidermal basement membrane [6]. The cytoskeleton of each keratinocyte is linked by desmosomes, and in basal keratinocytes, it is linked to the basement membrane by hemidesmosomes. The keratinocyte cytoskeleton contains large amounts of keratin intermediate filaments, which are bundled together like ropes to form tonofilaments with high tensile strength. The buildup of specialized keratin filaments in each epidermal layer is called keratinization, a key part of cellular differentiation in the epidermis. Desmosomes of the stratum granulosum are modified by addition of corneodesmosin, and by other changes, to become corneodesmosomes in the stratum corneum [4]. Many diseases of epidermal fragility, i.e., mechanobullous diseases and pustular diseases, cause skin lesions by disrupting desmosomes, hemidesmosomes, or the basement membrane. Dermis The dermis (corium) is a thick, discrete, organized layer of extracellular matrix (collagens, etc.) that provides structure, toughness, and flexibility to the skin, and it supports the epidermis and adnexa as well as blood vessels, lymphatic vessels, and nerves found within it (Fig. 2) [1]. The dermis is divided into a thin superficial papillary layer with more loosely arranged matrix and finer collagen bundles and a thicker deep reticular layer that is more densely packed with coarser collagen bundles. The dermis is composed primarily of collagen, mostly types I and III, for strength, elastin for elasticity, and proteoglycans, like hyaluronic acid, for hydration and turgor pressure. In cats, the dermis has a scalloped deep margin (Fig. 1) with projections that connect to the lobular septa of the panniculus below. Dermal vessels are arranged in three sheet-like plexuses of arteries and veins that are located just below the epidermis, in the mid dermis, and in the deep dermis at the junction with the panniculus [7]. The dermis contains microscopic bundles of smooth muscle attached to hair follicles, called erector pili muscles, and free bundles in the dermis of teats (nipples) and scrotum [1, 2]. Also in the scrotum, the dartos tunic of the testis extends to the panniculus where it contributes smooth muscle and collagenous stroma. Small bundles of skeletal muscle extend to the dermis in facial and perineal areas only. Adipocytes are not normal constitutes of cat dermis and are part of the panniculus. Mesenchymal cells maintain the dermal matrix and include fibrocytes (Fig. 2), which are spread individually throughout the dermis, as well as pericytes and Schwann cells that are localized around blood vessels and nerves, respectively. Low numbers of immune cells such as mast cells, dermal dendritic cells, lymphocytes, and basophils can be found in a healthy dermis where they are usually individualized and localized more to superficial perivascular and less to interstitial areas. Mast cells are common in the dermis of cats with 4 to 20 mast cells visible per 400x microscopic field on histology (Fig. 2) [8]. Neither neutrophils nor eosinophils are found in normal dermis or epidermis. Structure and Function of the Skin 9 VetBooks.ir Panniculus The panniculus (hypodermis, subcutis) is composed of discrete sheetlike layers of adipose, muscle, and fascia (Fig. 1) [1, 2, 9]. Immediately below the dermis, the panniculus adiposus (called the superficial adipose tissue) contains adipose arranged into lobules by thin fibrous septa (Fig. 1) [9]. Deeper, the panniculus fibrosus (superficial fascia) is a thin, variably discrete, sheet of fibrous tissue that connects to the lobular septa of the panniculus adiposus. Coursing within the fascia is a thin layer of striated muscle called the panniculus carnosus (cutaneous trunci) [1, 2]. The panniculus carnosus is more developed dorsally on the trunk (Fig. 1), neck, and proximal limbs and tapers away on the ventral abdomen (Fig. 4) and limbs to become absent on the extremities. Depending on the body region, like the extremities, the panniculus fibrosus merges with the deep fascia that surrounds the muscle of the skeleton or periosteum [8]. However, in some areas, like the ventral trunk, another layer of lobular adipose (called the deep adipose tissue) is present below the Fig. 4 Ventral mid abdomen, cat. The panniculus has three main layers: panniculus adiposus, panniculus carnosus, and panniculus fibrosus. The panniculus adiposus is composed of lobules of adipose just below the dermis, called the superficial adipose tissue (SAT), and in some body regions, a second layer which is deeper, called the deep adipose tissue (DAT), is also present. The panniculus fibrosus (PF) is a sheet of fibrous tissue (superficial fascia) that connects to the thin fibrous septa of adipose and supports the panniculus carnosus (PC), which is diminished ventrally. 40X magnification. Hematoxylin and eosin VetBooks.ir 10 K. E. Linder panniculus fibrosus that is an additional deeper portion of the panniculus adiposus (Fig. 4) [9]. The panniculus adiposus is the thickest on the trunk, especially on the ventrum of the cat, where it can be measured in centimeters in obese patients, and it is mostly absent in the extremities. The panniculus is specialized to form cushions in footpads (Fig. 3), which are composed of lobules of adipose with thickened fibrous septa.1.2 Arteries, veins, nerves, and lymphatic vessels are present in the panniculus and pass through to the dermis above. Skin Adnexa (Skin Appendages) Hair Follicles Hair follicles produce hairs that cover nearly the entire body of the cat except for small areas like the mucocutaneous junctions, external genitalia, teats, planum nasale, and footpads [1, 2]. The density of hairs on the cat is higher, 25,000 per square centimeter, compared to the dog, 9000 per square centimeter, but the density varies by breed and anatomical location. Most hair follicles in the cat are a compound type in which several hair follicles share a single follicle opening (follicular ostium), while fewer are of a simple type with one hair follicle per ostium. Primary hair follicles are larger and produce larger hair shafts (guard hairs, outer coat hairs), while secondary hair follicles are smaller and produce smaller hair shafts (undercoat hairs). In cats, most hair follicles are grouped such that a single, simple, large primary hair follicle (central primary hair) is surrounded by two to five compound follicles, each with a primary hair(s) (lateral primary hair(s)) and 3–12 secondary hairs, with numbers partly depending on age [1, 2, 10, 11]. The tail lacks this arrangement and hair follicles are larger [2]. Primary hairs of cats are much thinner, 40–80 micrometer in diameter, compared to dogs, 80–140 micrometer, whereas the secondary hairs of cats are 10–20 micrometer and those of the dog are 20–70 micrometer. Most hair follicles lay in the skin at an angle to the epidermal surface such that their hair shafts all point caudally on the head and trunk and distally on the limbs (Fig. 1). In the dermis, the ectal side (outside) of the hair follicle is closer to the epidermis (acute angle), and the ental side (inside) is further from the epidermis (obtuse angle). Specialized sinus hair follicles (vibrissae or whiskers) are very large simple hair follicles surrounded by a blood sinus and have complex innervation and sensory tactile function (slow-adapting mechanoreceptor) (Fig. 5) [1, 2, 8]. Sinus follicles produce vibrissae that are large tactile hairs that vary greatly in length. Sinus hairs are found on the face (muzzle, eyebrows, lips), and palmar carpus, and variably on the neck, forelimbs, and paws of cats and are arranged individually, in small clusters, or in short rows in some areas on the face. A second tactile hair type, the tylotrich hair, arise from follicles that are slightly larger and more richly innervated than those of primary hair follicles and contact an adjacent sensory tylotrich pad (touch dome) when compressed [1, 2]. Tylotrich hairs are scattered individually, in low density, throughout most of the haired skin. VetBooks.ir Structure and Function of the Skin 11 Fig. 5 Sinus hair follicle (vibrissae follicle), face, cat. The sinus follicle is a very large simple hair follicle that produces a large hair shaft (HS), or whisker, and is named for a large blood-filled sinus (S) that surrounds the follicle. The sebaceous gland (SG) and dermal papilla (DP) are annotated. 4X magnification. Hematoxylin and eosin Hair follicles form during development as specialized epithelial down-growths of the epidermis (ectodermal origin) interacting with clusters of specialized mesenchymal cells (mesodermal origin) called the dermal papilla [10]. A fully formed hair follicle is a linear, layered, tubular epithelial structure that opens superficially at the follicular ostium and forms a solid bulb at its deep base with an invagination that encircles the dermal papilla (during anagen only) [1]. The erector pili muscle is a smooth muscle, and it originates in the dermis from the epidermal basement membrane and inserts on the ental side of the hair follicle [1]. This muscle elevates the hair shaft on the skin surface, for example, in behavior responses and with cold temperatures to trap more insulating air in the hair coat. The hair follicle epithelium is encased in a basement membrane (the glassy membrane) that is surrounded by a thin layer of collagen and specialized dermal fibrocytes, called the dermal root sheath or fibrous sheath [1]. The perifollicular dermis is richly supplied by small blood vessels that branch from all three dermal plexi but most prominently the mid dermal plexus [7]. Hair follicles in the anagen phase can extend into the panniculus adiposus (Fig. 1). Hair follicles continually cycle to produce, hold, and shed hairs [10, 12]. The hair growing phase (anagen, Fig. 6) transitions through a short involution phase (catagen) and then ends in a resting phase (telogen, Fig. 6) in which a hair is retained or kenogen in which a hair is not retained (also called hairless telogen) [12]. A resting hair shaft is actively shed (exogen) usually when the cycle begins again. Hair K. E. Linder VetBooks.ir 12 Fig. 6 Rostral chin, cat. Large primary hair follicles in the growing anagen phase and the resting telogen phase of the hair follicle cycle. A) In fully developed anagen, the hair bulb (HB) encases the dermal papilla (DP) and actively produces the hair shaft (HS) and inner root sheath (IRS). B) In fully developed telogen, the hair bulb and internal root sheath are absent and the external root sheath (ERS) regresses to surround the hair shaft, while the dermal papilla (DP), remains connected by only an epithelial strand (ES). The hair shaft stops growing, and its pointed end (club hair) is sealed by brightly eosinophilic trichilemmal cornification. 20X magnification. Hematoxylin and eosin shedding in the cat is mosaic (nonsynchronous) [10]. The duration of phases varies by age, breed, season, etc. [13] For example, the length of the hair shaft depends on the length of the anagen phase – longer hair is due to a longer anagen phase. The hair follicle has three zones (segments) called the infundibulum, isthmus, and inferior portions [12]. The infundibulum is the superficial, permanent, non-cycling segment that morphologically resembles the epidermis and attaches to it [1]. The isthmus and the deeper inferior portions change morphologically with the hair follicle cycle and have five main components, some only being present during the anagen phase (Fig. 6) [1, 12]. First, the inner root sheath surrounds the central follicle lumen and has its own three layers, an inner cuticle, Huxley’s layer, and outer Henle’s layer. The raised exposed edges of overlapping cuticle cells point internally (toward the hair bulb) and interlock with opposite facing hair shaft cuticle cells. The inner root sheath is only present during anagen (Fig. 6) when its keratinocytes continually migrate up in concert with the growing hair shaft, cornify, and shed to the infundibular lumen. Second, the companion layer is a single layer of cells that separates the VetBooks.ir Structure and Function of the Skin 13 inner rooth sheath from the external root sheath. Third, the external root sheath is several keratinocytes thick, it encases the inner root sheath, and it is contiguous with the infundibulum. Forth, the hair bulb, forms during anagen and is composed of hair matrix cells arranged in concentric layers that generate each of the layers of the inner root sheath, the companion layer, and the hair shaft (Fig. 6). Finally, the fourth part, the derma papilla (follicular papilla), is encased by an invagination of the hair bulb (Fig. 6). The dermal papilla is composed of mesenchymal spindle cells, blood vessels, and nerves, and its molecular communication with the hair matrix cells partly controls follicle cycling, hair shaft formation, and hair shaft pigmentation. The hair shaft is formed by cornification of hair bulb cells (hair matrix cells), which makes it rigid, and contains three concentric layers, the outer cuticle, the cortex, and the inner medulla [1]. The hair shaft cuticle is a single layer of overlapping flattened cells in which exposed cell edges point outward (away from the hair bulb). The cortex is compacted and is nonpigmented or variably pigmented. The medullary cells have an open structure that in some follicles highlights an empty nuclear profile – primary hairs have a medulla but secondary hairs do not. The medulla may be pigmented or non pigmented. The outer end of the hair shaft is pointed in a long thin taper, while the inner end (hair root) is either connected to the soft viable hair bulb during anagen or is sealed-off in telogen by trichilemmal cornification to form a short, rigid, pointed taper with a rough surface (club hair) (Fig. 6). Clinically, hair shafts are epilated and examined microscopically (trichogram) to identify the stage of the hair follicle cycle, primary or secondary status, and any hair shaft abnormalities. Anagen phase hair bulbs indicate active hair growth and, on trichogram, are recognized to be soft, flexible, rounded, and often axially deviated and pigmented when hair is pigmented. Telogen phase hairs (club hair) indicate resting hair follicles and have short tapered ends that are rough externally, rigid, and not axially deviated and are nonpigmented in hair that is pigmented or nonpigmented. Skin Glands In the cat, sebaceous glands are small, simple or compound, lobulated alveolar glands that connect to the lower infundibular lumen of hair follicles (pilosebaceous unit) by a very short duct lined by stratifed and cornifying epithelium [1, 2, 14]. At the edge of lobules (peripheral zone), a single thin layer of cuboidal reserve cells divides and differentiates to form larger polygonal lipid-vacuolated cells called sebocytes centrally (maturational zone), which shed to the lumen (holocrine secretion) to form sebum. In the cat, cytoplasmic vacuoles of sebocytes are very small and very uniform in size. Larger, often multilobulated, sebaceous glands are present on the face, especially the chin (Fig. 7; submental organ), ear base, dorsum, anal-rectal junction, palmar carpus (carpal gland), and interdigital paw skin. Meibomian glands (tarsal glands) are large sebaceous glands of the eyelid margin, especially the upper eyelid (Fig. 8) [2]. Sebaceous glands are not found in the planum nasale or the footpads. Apocrine glands (epitrichial sweat glands) and eccrine glands (atrichial sweat glands) in cats are simple coiled tubular glands that secrete via a duct to the deep VetBooks.ir 14 K. E. Linder Fig. 7 Rostral chin, cat. Sebaceous glands (SG) in the chin area (submental organ) are very large and multilobulated, and the dermis (D) is expanded to support the larger sebaceous glands in addition to the apocrine glands (AG), hair follicles (HF), and epidermis (E). 4X magnification. Hematoxylin and eosin Fig. 8 Upper eyelid, cat. The upper eyelid is lined by haired skin (HS) externally and by mucosa (M) of the palpebral conjunctiva internally. Meibomian glands (MG) are enlarged sebaceous glands that align in a single long row that tracks the mucocutaneous junction. 4X magnification. Hematoxylin and eosin infundibulum of primary hair follicles (epitrichial) (Fig. 7) and to the footpad surface (atrichial) (Fig. 3) [1, 2, 14]. Glands are lined by cuboidal to low columnar cells that secrete by the release of apical blebs of the cytoplasm to the gland lumen and then to a thin duct lined by a bilayer of short cuboidal cells. A few myoepithelial cells surround the gland. Ceruminous glands are modified apocrine glands in the external ear canal (see below). Eccrine glands are not found on the planum nasale. VetBooks.ir Structure and Function of the Skin 15 Fig. 9 Proximal dorsal tail, cat. The dorsal tail gland (DTG) of the cat, also called the supracaudal gland, is non-discrete and is composed of hepatoid glands on hair follicles along most of the dorsal tail. Erector pili muscles (M) are largest on the proximal dorsal tail and originate from the basement membrane of the epidermis (E) and insert on hair follicles in the dermis (D). 4X magnification. Hematoxylin and eosin In the cat, the dorsal tail gland (Fig. 9, supracaudal gland) is formed by hepatoid glands located on hair follicles of the dorsal tail, especially proximally [15]. Feline hepatoid glands are a mixed lipid and protein secretion type and thus appear very pale, eosinophilic, and moderately vacuolated in hematoxylin and eosin-stained histology sections compared to brightly eosinophilic and non-vacuolated hepatoid glands (circumanal glands) of the dog, which produce primarily protein [15]. This is also the situation for hepatoid glands present on the anal sacs of cats. Anal sacs (perianal sinuses) are paired in the cat and are located in the subdermal tissue of the perineum bilaterally (Fig. 10) [1, 2]. The anal sac and its short, duct-like, narrow opening to the anal-rectal skin junction are thin walled and lined by stratified squamous epithelium with an orthokeratotic pattern of cornification, which are supported by a thin layer of dermal matrix. Apocrine glands and large hepatoid glands of the anal sac (Fig. 10) are grouped in this matrix along the anal sac margin and empty to it [2, 14]. The mammary gland is a compound tubulo-alveolar gland arranged by septa into lobules and lobes where each gland empties via a branched ductular system to a teat (nipple) [1]. Glandular secretions pass through intralobular, to interlobular ducts, to lactiferous ducts, and then to a teat sinus (teat cistern), all of which are lined by either a simple layer or a bilayer of cuboidal cells. In the cat, the teat sinus empties externally through four to seven papillary ducts that are lined by stratified squamous epithelium. The teat dermis contains free bundles of smooth muscle but scant other adnexa. In the cat, four mammary glands are organized in linear mammary chains on the right and left side of the ventral abdomen. VetBooks.ir 16 K. E. Linder Fig. 10 Anal sac and associated glands, cat. The anal sac (AS) is thin walled and lined by stratified squamous epithelium. Multifocal apocrine glands (AG) and hepatoid glands (HG) empty to the anal sac. 4X magnification. Hematoxylin and eosin Claws The cat claw is a very specialized and complex structure composed of a cornified claw sheath (claw horn, claw) that is formed by stratified epithelium and supported by specialized dermis (corium) [16]. The claw in the cat is a highly tapered (sharply pointed) curved, and ventrally flattened cone that has a rounded wall dorsally, flattened blades on its slides, and a narrow cutting ridge ventrally. Proximally, a band of claw matrix cells continually divide and differentiate to supply keratinocytes for growth of the claw. More distally, the claw bed (claw plate) cells provide sliding adhesion that allows epithelial cells to move distally and to cornify into the rigid claw. Cats sharpen their claw tips by repeat shedding of a cornified horn cap that is promoted by scratching [16] – shed horn caps are sometimes mistaken for a sloughed claw. The claw encases the claw dermis and the closely apposed unguicular process of the third phalanx. The hard cornification of the rigid claw is bordered by soft cornification where it is contiguous with the skin fold (claw fold). The claw fold is large on the dorsal and lateral margins of the claw and minimal below. Below the claw centrally, a small sole first merges with the narrow skin fold, which merges with palmar or plantar digital pad [16]. The claw fold is modified and elaborated (claw sac, etc.) in the cat to allow claw retraction. External Ear (Chapter, Otitis) The skin of the pinna and external ear canal (external acoustic meatus) are lined by stratified squamous epithelium with an orthokeratotic pattern of cornification, which is supported by a thin dermis [2, 17]. Skin adnexa are present on all surfaces but are smaller and less densely placed in the inner ear pinna (concave pinna) and especially in the external ear canal in comparison to the outer pinna (convex pinna) (Figs. 11 and 12). Hair follicles and sebaceous glands are in all of these locations 17 VetBooks.ir Structure and Function of the Skin Fig. 11 External pinna, cat. The external pinnae contain a sheet of elastic cartilage (EC) centrally that is lined by dermis (D) and epidermis (E) on the convex (top of image) and concave (bottom of image) sides. Adnexa, including hair follicles (HF), sebaceous glands, and apocrine glands, are more numerous and larger on the convex surface compared to the concave surface. 4X magnification. Hematoxylin and eosin Fig. 12 Horizontal ear canal (cross section), cat. The ear canal is lined by a thin epidermis (E) and dermis. The inset demonstrates the small sparse adnexa of the ear canal in the dermis (D), including a hair follicle (HF), a sebaceous gland (SG), and a ceruminous gland (CG). 4X magnification and 20x magnification (inset). Hematoxylin and eosin but are in a low density in the external ear canal. Apocrine glands are present on the convex and concave pinna. Modified apocrine glands, called ceruminous glands, are in the portion of the external ear canal that is supported by the annular cartilage (Fig. 12) and are more numerous in the deep one third of the canal [17–20]. These glands connect to the sparse follicles or directly to the epidermis [17]. Ceruminous gland secretions mix with sebum, epidermal surface lipids, and desquamated corneocytes to form a waxy protective material called cerumen. Centrifugal epithelial migration of keratinocytes off of the external tympanic membrane and on to the external ear canal helps to clear cerumen from the surface of the tympanic membrane, which is located at the deep extent of the ear canal [19]. 18 K. E. Linder VetBooks.ir Skin Pigmentation The skin derives its color from pigmentation (melanin pigment); blood in vessels (red heme pigment); the endogenous reflective properties of the epidermis, dermis, and adnexa; as well as the quality of light being reflected [8]. Melanin pigment is composed of two types, brown to black eumelanin and red to yellow pheomelanin, that are expressed variably to produce a color range. From neural crest, melanocytes migrate during development into the epidermis, follicles, and claws and then produce melanin pigment in membrane-bound cytoplasmic organelles called melanosomes. Through dendritic processes, a melanocyte transfers pigmented melanosomes to a certain number of local keratinocytes, and together, they are called an epidermal melanin unit (or follicular melanin unit in the hair bulb). The amount and type of melanin produced and the degree of dispersal of melanosomes to keratinocytes affect the pigment intensity, ranging from a pale dilute to a very dark color. Melanocytes in the anagen hair bulb deliver melanosomes to growing hair shafts, continuously or episodically, and the latter produces color banding (agouti, etc.), which is partly controlled by the dermal papilla. Many coat color variations (Chapter, Coat Color Genetics) in cats are due to inheritance of alleles that alter melanocyte distribution or presence/absence, melanosome dispersal, and/or the amount and type of melanin produced. Clinically, the loss of pigment (leukoderma, leukotrichia) is due to disruption of the epidermal melanin unit, and/or follicular melanin unit, and thus can result from diseases that injure melanocytes and/or keratinocytes. General Skin Functions The skin has many important functions that, when compromised by disease, have significant consequences for the patient [8]. Physical Barrier Function The skin protects the body from physiochemical injury. It prevents entry of foreign materials, parasites, and infectious agents while, at the same time, preventing loss of water and fluid components (electrolytes, macromolecules, etc.) from the body. To do this, the epidermis and dermis provide the toughness of the skin, and hair reduces frictional injury. The panniculus provides a cushion to injury especially in footpads. Skin pigment and hair block damaging solar radiation. The stratum corneum, especially the lipid envelop, seals the epidermis to water loss, whereas deeper epidermal layers also contribute, for example, via tight junctions in the stratum granulosum. Corneocytes are shed continuously from the skin surface, eliminating attached microorganisms. Claws even serve as offensive physical defense against attack of other animals and as tools needed by cats for climbing and handling of prey. Structure and Function of the Skin 19 VetBooks.ir Immune Defense More than just a passive physical barrier, the skin immune system actively identifies, blocks, and eliminates pathogens through actions of the innate (keratinocytes, mast cells, basophils, natural killer cells, dendritic cells, sebum, etc.) and acquired immune skin systems (T-cells, B-cells, dendritic cells, etc.). Additional cells, neutrophils, eosinophils, and macrophages are recruited to the skin through its vasculature and contribute to skin defense and immune function. Sebum and stratum corneum constituents contribute to skin surface pH, and fatty acid composition favors skin colonization by beneficial bacterial commensals and limits pathogens. Interestingly, the skin helps to maintain peripheral immune tolerance, by assisting the thymus in educating the acquired immune system on self and non-self antigens. Thermoregulation The skin is a key organ of thermoregulation that both works to prevent heat loss and to promote it, as needed, to optimize core body temperature. The hair coat and adipose are the main thermal insulating barriers, and the former can be modified by erector pili muscles moving the hair and controlling its density. Skin blood flow is actively promoted, restricted, and/or shunted to alter core heat transfer to the skin, especially in the distal limbs and ears. Pigment in hair and epidermis absorbs light energy, leading to heating of the skin. Sweating promotes cooling through evaporation. Metabolic Functions The skin has numerous metabolic functions; many maintain skin homeostasis, while others also serve systemic functions. For example, vitamin D is activated in the epidermis via exposure to sunlight. And, after further activation in the liver and kidney, vitamin D impacts epidermal proliferation and differentiation in the skin as well as contributes to calcium homeostasis of blood and bone, among many other functions, systemically. Expression of p450 enzymes in the epidermis means that xenobiotic compounds can be processed there. The panniculus adiposus contributes much of the bodies’ capacity to store energy in the form of lipids. Similarly, dermal collagen is a protein reservoir. The epidermis, hair follicles, and skin glands produce useful substances but also eliminate endogenous and exogenous metabolic constituents, such as some toxins (lead in hair). Communication The skin glands produce scents that are important for olfactory communication in carnivores. Erector pili muscles, especially along the back and tail, elevate the hair, VetBooks.ir 20 K. E. Linder changing the physical hair coat appearance, to visually communicate behavior status and warning signals to other animals, and to disperse pheromones. Skin and hair coat pigmentation, although modified dramatically in many domestic cats by human selection pressures, provide camouflage important for carnivores while hunting. Sensory Perception The skin is a major organ of sensation, and its sensory nerve endings distinguish temperature (hot and cold), pain, pruritus, burning, touch, etc. References 1. Monteiro-Riviere N. Integument. In: Eurell JA, Frappier BL, editors. Dellmann’s textbook of veterinary histology. 6th ed. Iowa: Blackwell Publishing Professional; 2006. p. 320–49. 2. Strickland JH, Calhoun ML. The integumentary system of the cat. Am J Vet Res. 1963;24:1018–29. 3. Monteiro-Riviere NA, Bristol DG, Manning TO, et al. Interspecies and interregional analysis of the comparative histologic thickness and laser Doppler blood flow measurements at five cutaneous sites in nine species. J Invest Dermatol. 1990;95:582–6. 4. Matsui T, Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol. 2015;27:269–80. 5. Bowser PA, White RJ. Isolation, barrier properties and lipid analysis of stratum compactum, a discrete region of the stratum corneum. Br J Dermatol. 1985;112:1–14. 6. Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Annu Rev Pathol. 2016;11:175–97. 7. Meyer W, Godynicki S, Tsukise A. Lectin histochemistry of the endothelium of blood vessels in the mammalian integument, with remarks on the endothelial glycocalyx and blood vessel system nomenclature. Ann Anat. 2008;190:264–76. 8. Miller WH, Griffin CE, Campbell K. Muller & Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. p. 1–56. 9. Stecco C. Subcutaneous tissue and superficial fascia. In: Functional atlas of the human fascia. Philadelphia: Elsevier; 2015. p. 21–30. 10. Meyer W. Hair follicles in domesticated mammals with comparison to laboratory animals and humans. In: Mecklenburg L, Linek M, Tobin D, editors. Hair loss disorders in domestic animals. Iowa: Wiley-Blackwell; 2009. p. 43–61. 11. Zanna G, Auriemma E, Arrighi S, et al. Dermoscopic evaluation of skin in health cats. Vet Dermatol. 2015;26:14–7. 12. Welle MM, Wiener DJ. The hair follicle: a comparative review of canine hair follicle anatomy and physiology. Toxicol Pathol. 2016;44:564–74. 13. Ryder Ryder ML. Seasonal changes in the coat of the cat. Res Vet Sci. 1976;21:280–3. 14. Jenkinson DM. Sweat and sebaceous glands and their function in domestic animals. In: von Tscharner C, Halliwell REW, editors. Advances in veterinary dermatology, vol. 1. Philadelphia: Bailliere Tindall; 1990. p. 229. 15. Shabadash SA, Zelikina TI. Detection of hepatoid glands and distinctive features of the hepatoid acinus. Biol Bull. 2002;29:559–67. 16. Homberger DG, Ham K, Ogunbakin T, et al. The structure of the cornified claw sheath in the domesticated cat (Felis catus): implications for the claw-shedding mechanism and the evolution of cornified digital end organs. J Anat. 2009;214:620–43. VetBooks.ir Structure and Function of the Skin 21 17. Strickland JH, Calhoun ML. The microscopic anatomy of the external ear of Felis domesticus. Am J Vet Res. 1960;21:845–50. 18. Fernando SDA. Microscopic anatomy and histochemistry of glands in the external auditory meatus of the cat (Felis domesticus). Am J Vet Res. 1965;26:1157–61. 19. Njaa BL, Cole LK, Tabacca N. Practical otic anatomy and physiology of the dog and cat. Vet Clin North Am Small Anim Pract. 2012;42:1109–26. 20. Tobias K. Anatomy of the canine and feline ear. In: Gotthelf L, editor. Small animal ear diseases, an illustrated guide. 2nd ed. St. Louis: Elsevier-Saunders; 2005. p. 1–21. VetBooks.ir Coat Color Genetics Maria Cristina Crosta Abstract The various breeds of cats differ considerably one from the other, not only in terms of their different morphological features but also in terms of the colour, length, structure and texture of their coat. The feline coat has various functions, such as aesthetic and mimetic, heat regulation, perception of the body position through vibrissae and tylotrich pads, social and sexual communication, and acts as a barrier against mechanical, physical and chemical insults. In the first part of this chapter, the morphology and cycle of the hair are briefly introduced, including melanin synthesis. In the second part, the genetics of hair length, structure, texture, colour and colour patterns are detailed, providing a good description to understand the specific functional aspects of the feline coat. The various breeds of cats differ considerably one from the other, not only in terms of their different morphological features but also in terms of the colour, length, structure and texture of their coat. The Coat Cat show organisers classify cat breeds according to three main categories: • Longhair cats, the representatives being the Persian (in all colour shades and varieties), the British Longhair, the Selkirk Rex and the Highland Fold Images by Lia Stein M. C. Crosta (*) Clinica Veterinaria Gran Sasso, Milan, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_2 23 VetBooks.ir 24 M. C. Crosta • Medium-length hair cats, e.g. Norwegian Forest, Maine Coon, Balinese, Birman • Shorthair cats, e.g. European, Chartreux, Russian Blue, British Shorthair Within these categories, the coat is then classified according to pattern, colour and colour distribution. Function The coat has various functions: • Aesthetic and mimetic; • Heat regulation, in function of the length, thickness and density of the coat, as well as of its colour and shine (a light-coloured coat reflects light better and allows to keep body temperature constant); • Perception of body position (vibrissae, tylotrich pads); • Social and sexual communication, thanks to both the visual effect and as support to pheromones; • Barrier against mechanical, physical and chemical insults. Whatever its length, a cat’s coat is made to protect the animal and help it adapt to its environment, like in the case of cats that live in very cold climates. The coat of these cats (Maine Coon, Norwegian Forest cats) consists of long primary hairs (basic coat) and a thick undercoat. The hair of a Norwegian Forest cat is water-repellent. This trait makes its coat especially suited for the adverse weather conditions of its country of origin. In shows, sometimes judges assess this feature by dripping some water over its coat. Another example is the Turkish Van, a cat that has a very thick coat in winter and that sheds in a spectacular manner in summer. In fact, in this season it loses almost all of its fur, to the point of looking like a shorthair cat. This breed has adapted to the climate of Central Anatolia, its region of origin, where there is a great difference in temperature between winter (−20 °C) and summer (+40 °C). Morphology Macroscopically speaking, regardless of length, cat hair can be classified as: 1. Primary hair (guard hair) 2. Secondary hair (down hair). Like all carnivores, cats have compound hair follicles. This means that the coat is comprised of many small units. Each unit consists of two to five larger hairs VetBooks.ir Coat Color Genetics 25 (primary hairs) surrounded by clusters of smaller hairs (secondary hairs). To each primary hair are associated from five to twenty secondary hairs. Each primary hair has its own sebaceous gland, a sweat gland and an arrector pili muscle. A primary hair emerges through the surface of the skin through its own independent infundibulum. Secondary hairs are associated only to one sebaceous gland and emerge from a common infundibulum. It is estimated that, in cats, for each square cm of skin there are anywhere from 800 to 1600 of these units. From a functional point of view, hair can also be classified as: 1. Protection hair: these hairs are straight and thicker. 2. Intermediate hair: these hairs are thinner than protection hairs and more variable in cross diameter. They grow in the opposite direction of the underhair and play an isolating and protective role together with the underhair. 3. Underhair: these hairs are short and thin and have a crimped appearance, sometimes curly. In winter, they trap warm air and create a veritable insulating barrier against the cold, while in summer they limit the absorption of heat coming from the outside. The proportions vary according to breed: • All three hair types can be present, but they can be highly modified (e.g. Devon Rex). • One can be missing (e.g. protection hair in the Cornish). • One can be more abundant than the others (e.g. underhair in Persians). • One can be very scarce (e.g. underhair in the Korat). There are two types of tactile hairs: • Vibrissae: they grow on the muzzle, around the eyes, in the throat region and on the palmar face of the carpi. These hairs are thick and contain specialised nerve structures. • Tylotrich hairs: they are distributed all over the body and consist of a larger than normal hair follicle containing a single short hair and surrounded by a capsule of neurovascular tissue at the level of the sebaceous gland. These hairs are believed to be slow-adapting mechanoreceptors. The hair shaft is made up of three concentric structures, the medulla, the cortex and the cuticle. The medulla is the inner structure of the hair and consists of longitudinal rows of cells that are solid close to the root and that progressively fill with air and glycogen as they rise towards the tip. The cortex forms the middle structure of the hair and is formed by hard and fuse- shaped cells with the longer axis parallel to the hair’s axis. These cells contain the pigment that gives the hair its colour. VetBooks.ir 26 M. C. Crosta The cuticle is the outermost structure of the hair and is made up of scales (in humans they are imbricate, like the tiles of a roof, while in cats they are triangular with a spinous edge and with the hooked free edge facing the direction of the hair tip). Hair Growth Cycle The hair follicle is the structure from which the hair grows. It consists of an upper section called ‘infundibulum’, an intermediate section called ‘isthmus’, and a deep section that is the ‘bulb’. The infundibulum and the isthmus are the permanent portions of the hair, while the bulb is present only in the active growth phase. The hair bulb consists of matrix cells (that generate the hair itself and the internal sheath that contains the root) and of pigment-producing cells called melanocytes. The hair follicle has an active, cyclic growth phase called anagen and a rest phase called telogen. They are separated by a transition phase called catagen. The duration of the anagen phase is hereditary and determines the final length of the hair. In this phase, the dermal papilla is very well developed and the cells of the bulb’s matrix actively multiply to form the hair. The bulb’s melanocytes actively produce pigment (melanin) and distribute it to the hair’s cells that progressively migrate towards the surface of the skin. During the transition phase called catagen, pigment production stops completely and the production of cells by the matrix progressively slows down to a stop. The last cells produced therefore are entirely pigment-less and this explains why in this phase of the cycle the section of the hair closest to the skin is also the lightest. During telogen, the follicle, in a resting phase, has shrunk to one third of its length and the dermal papilla has transformed into a small mass of undifferentiated cells. Hair shedding does not occur simultaneously throughout the coat but according to a ‘mosaic’ shedding pattern. This is because neighbouring hair follicles are all at different stages of growth. The hair grows to a pre-set length that can vary according to the body region and is genetically determined. The active growth phase and therefore hair growth speed is highest in summer and lowest in winter. Indeed, it is thought that in summer 50% of the follicles are in telogen, while in winter this percentage rises to 90%. Melanin Synthesis Melanin is the pigment responsible for colouring skin and hair. This is not its only function, however. By distributing through the cytoplasm, it protects the cells of VetBooks.ir Coat Color Genetics 27 Fig. 1 The synthesis of eumelanin and pheomelanin L-Tyrosine Tyrosinase +Cu L-DOPA Tyrosinase +Cu DOPAQUINONE + Cysteine Pheomelanin Eumelanin the epidermis and of the deeper skin layers from ionizing radiation and from ultraviolet (UV) light. Melanin also eliminates the toxic free radicals generated by the skin’s cells following exposure to sunlight and in the course of inflammatory processes. Melanin synthesis is genetically determined (Fig. 1). Its production may be stimulated by several factors, such as exposure to ultraviolet radiation from the sun, and may be affected by hormone unbalance. There are various types of melanin, but the basic types are eumelanin and pheomelanin. Eumelanin granules are contained in melanosomes and are responsible for the brown-blackishblack colour. Pheomelanin granules are also contained in melanosomes and impart a yellow-brownish-red colour. There are many intermediate variations between these two types. Pheomelanin features a higher sulphur content compared to eumelanin. Although different, eumelanin and pheomelanin have a common metabolic life. An enzyme called tyrosinase in the presence of oligoelements, such as copper, transforms tyrosine first into DOPA and then into dopaquinone and from there, through a sequence of oxidations, into the various kinds of melanin pigment. The importance of the role played by this enzyme in VetBooks.ir 28 M. C. Crosta pigment synthesis is proven by the fact that the mutation of the structural gene of tyrosinase is responsible for many forms of albinism in humans and in animals. The synthesis of eumelanin requires high concentrations of tyrosinase, while that of pheomelanin needs lower concentrations but requires cysteine. Tyrosinase is heat-sensitive, which means that its concentration decreases in proportion to the increase in temperature. In body areas where the temperature is lower (legs, for example) thanks to the increase in enzyme activity there is a higher deposit of eumelanin granules, and this gives the coat a darker coloration. This explains why, when the coat of a black cat is observed closely in the trunk area, a lighter coloration is seen at the base, while in the muzzle areas and on the legs (that are colder areas), the colour is darker. The Genes Controlling Hair Length, Structure and Texture Although from a morphological viewpoint we distinguish three kinds of cat coats – long, semi-long and short – from a genetic viewpoint, in terms of hair length, the coats are two – shorthair and longhair (Figs. 2, 3 and 4). The genes described in this chapter are summarized in Table 1. A definition of genetic terms is provided in Box 1. Fig. 2 Long-haired cat Coat Color Genetics VetBooks.ir Fig. 3 Semilong-haired cat Fig. 4 Short-haired cat 29 30 M. C. Crosta VetBooks.ir Table 1 Main genes controlling coat colour in cats Genes controlling distribution of coat colour A Agouti a non-agouti Original wild colour, hair with alternated The colour bands on the single hairs disappear, light and dark bands and the result appears solid colour Genes controlling colour B Black b brown (or chocolate) bl light brown (or cinnamon) o non-orange O Orange – sex-linked because it is located on the X chromosome w normal colour W White dominant epistasis Genes controlling colour intensity C full Colour – even intensity all over cb burmese body cs siamese ca albino blue eyes c albino pink eyes Genes controlling colour density D Dense – normal hair colour density d dilution or maltesing Genes controlling hair colour development i complete development of pigment in I Inhibition of development of pigment in hair hair wb (or ch) no tipping Wb (or Ch) tipping Genes controlling white spot distribution s normal colour distribution in coat – no S piebald white Spotting – more or less extensive white spots white spots G normal colour distribution in coat – no g ‘gloves’ of the birman gloves Genes controlling tiger tabby patterns T mackerel Tabby (wild type) Ta abyssinian tabby tb blotched tabby (or classic tabby) Genes controlling and modifying hair length, structure and texture L shorthair l longhair R normal coat r Cornish Rex Re normal coat re Devon Rex Ro normal coat ro Oregon Rex rd normal coat Rd Dutch Rex rs normal coat Rs Selkirk Rex Hr normal coat hr Sphynx, Bambino, Elf, Dwelf hrbd normal coat Hrbd Don Sphynx, Peterbald, Levkoi wh normal coat Wh Wirehair VetBooks.ir Coat Color Genetics Box 1 • Homozygote/Heterozygote A homozygote is an individual having two identical alleles for one same trait (one coming from the mother and the other from the father). In fact, for each single trait each individual receives a pair of ‘corresponding’ genes called alleles, one inherited from each parent. If the individual inherits two identical alleles, that individual is homozygous for that specific trait (e.g. BB or bb). Conversely, if the individual inherits two different alleles from its parents, the individual will be a heterozygote (Bb). • Dominant and Recessive When an allele manages to express itself (phenotypic expression) both in a homozygous individual (BB) and in a heterozygous individual (Bb or Bbl), it is said to be dominant. If an allele expresses itself only in the homozygote, it is called recessive and is indicated with the lower case letter (bb). The dominant trait does not allow the recessive trait (b) to express itself. Two cats, one BB and the other Bb, shall both have a black coat, but BB is homozygous black while Bb is a black carrier of the chocolate colour that, being recessive to B, cannot be expressed. This is why in a genotype, 2 letters are used to indicate a trait (e.g. BB, Bb). If instead only one letter is used followed by a dash (e.g. B-), it means that we don’t know whether the individual is homozygous (BB) or heterozygous (Bb) for that same trait. In genetics, the dominant allele is indicated with an upper case letter, and usually uses to be the first letter of the gene to which it refers (B for Black, D for Dense). • Polygenes These are a group of genes (also called ‘modifiers’) the single action of which is often not quantifiable, but when working together have a cumulative effect and can change the action of the main gene. They affect quantitative traits (size, hair length, etc.), often quite significantly. • Epistasis Some genes have the capacity to prevent other genes from expressing themselves. Pheomelanin, for example, masks eumelanin; the non-agouti gene covers the tabby patterns; the W gene (dominant white) masks the expression of all of the other genes responsible for coloration and colour distribution (Fig. 31). 31 VetBooks.ir 32 M. C. Crosta Sometimes, the epistatic effect of the W gene is not totally effective. One often sees white kittens with a spot of colour (black, blue cream, etc.) on their head. This spot of colour, that totally disappears by the age of ten months or so, is nothing but the hidden colour the kitten will pass on to its progeny as an adult. All cats, independent of colour, are genetically tabby, i.e. they possess striping in their genotype (Fig. 32). In ‘self’ (solid colour) cats, striping is present but not visible because the a gene (non-agouti) does not allow striping to express itself (epistatic effect). The O gene (orange) transforms colour pigments into pheomelanin and through epistasis deactivates the loci coding for the production of eumelanin (Fig. 33). Moreover, the a gene (non-agouti) makes striping disappear (epistasis) only in eumelanic coats and has no effect on pheomelanic coats. This is why, in red cats, striping is always present. It is difficult to obtain an evenly red-coloured coat with intense red coloration (breeders have a hard task in doing this) because quite often residual stripes show up on the muzzle, tail and legs. Sometimes, in the attempt to diminish the undesired striping, varieties of red coats with excessively bleached coloration are selected. Unlike shorthair cats, in which the stripes are more evident, in the Persian these ‘defects’ are corrected by the hair length hair. Just like the other solid colour coats, the red coat must be even, i.e. each single hair must have the same intensity from the root to the tip, and its coloration must be as red as possible. Next to solid colour coats, also known as self, breeders select red tabbies in which the stripes are actually highlighted, in a curious game of contrast between the red background of the coat and the intense and prominent red of the pattern. • Density and Dilution Colour density is given by the dominant gene D responsible for dense pigmentation. Pigment granules are deposited one by one and evenly along the cortex and medulla of the hair. The entire surface of the granule reflects light, giving the hair a darker coloration. Coat coloration dilution is given by the recessive d gene (or Maltese gene) that causes a different distribution in space of the pigment granules without changing their shape. This different layout causes less light refraction and therefore the colour appears lighter. • Incomplete Dominance Incomplete dominance occurs when, in a pair of alleles, one allele does not totally dominate the other and the resulting individual shows intermediate traits (e.g. Tonkinese). • Agouti and Non-agouti This is an Indian term used to indicate a South American rodent. In genetics, it is used to describe the wild coloration of some mammals. The Agouti VetBooks.ir Coat Color Genetics 33 gene codes for the multiple banding of each single hair with yellow-greyish bands and a darker hair tip (ticking). Agouti allows the tabby alleles to express themselves. Agouti is the background colour against which one sees the stripes of a tabby coat (Fig. 34). The non-agouti gene codes for the masking of the bands of yellow-greyish colour on each single hair, making it still banded, but dark and very dark. Therefore, the coat appears to the eye of a single colour. It has an epistatic effect on tabby alleles. • Eumelanin, Pheomelanin and Tyrosinase The eumelanin granules determine brown, blackish or black coloration (B, bb, blbl). The pheomelanin granules determine red, yellow or orange coloration (O-). Eumelanin and pheomelanin are formed starting from the amino acid tyrosine. This process occurs thanks to the action of the enzyme tyrosinase (heat-sensitive) that oxidates tyrosine into various intermediate compounds (DOPA, dopaquinone). The C gene (colour intensity) codes for the enzyme’s correct structure, which means that its inactivation by high temperature is much slower than its production and, therefore, melanin is regularly produced and can provide full coloration of the entire coat. The Albino alleles (cb and cs) progressively cause a structural change in tyrosinase, making it especially heat-sensitive. In the warmer areas of the body, due to a lower influence of tyrosinase, there will be less pigment deposit (the body is warmer and therefore the coat colour will be paler), while in the cooler areas of the body (the extremities), there will be a greater deposit of pigment and therefore darker coloration. In the Burmese (cb), the enzyme’s structural modification causes the coat to change from black to dark brown and the eyes to become yellow or amber. In the Siamese coat, the cs gene makes the tyrosinase even more sensitive to heat, and therefore the difference between the colour of the body and that of the points (extremities) is much more evident and the eyes become blue (Fig. 35). The ca and c genes, instead, cause the destruction or lack of production of the enzyme, and therefore the coat is totally white and the eyes are blue and pink, respectively. Length Genes • short hair: L (dominant) • long hair: l (recessive) The original coat is short and is governed by a dominant gene labelled L. Long hair is given by its recessive mutant allele and is labelled l. Gene l is responsible not only for the long hair in Persian cats but also for the semi-long coats of the Maine Coon cat, Norwegian Forest cat, Siberian cat and Burmese cat. The various coat VetBooks.ir 34 M. C. Crosta lengths are due to the presence of polygenes or modifier genes. These are minor genes the single effect of which is too small to be observed. However, when they are acting together with other genes, they produce observable effects because together they are variably capable of changing the action of the main gene. Hair length is not the only trait to be taken into consideration. Structure and texture, too, are important elements of evaluation when examining the various kinds of coats. The coat can be more or less thick and abundant, and the three types of hair (protection hair, intermediate hair and underhair) can be normal and all present at the same time. Sometimes, like in the Devon Rex, there are significant changes, or one of the three types of hair can be missing, such as the protection hair in the Cornish Rex. The types of hair can be present in different proportions, like in the Korat that has almost no underhair or in the Persian that abounds in underhair, compared to the amounts of protection and intermediate hair. Structure and Texture • • • • • • • • r (recessive) Cornish Rex/German Rex re (recessive) Devon Rex ro (recessive) Oregon Rex Rd (dominant) Dutch Rex Rs (dominant) Selkirk Rex Wh (dominant) American Wirehair hr (recessive) Sphynx/Bambino/Elf/Dwelf Hrbd (dominant) Don Sphynx/Peterbald/Levkoy The most significant changes regarding hair structure and texture involve the r, h, Wh and Hrbd genes. r genes Cornish Rex A cat famous for its coat is the Cornish Rex. Its peculiar coat is due to the presence of the r gene. This gene codes for the lack of protection hairs and for deep changes in intermediate hair and underhair. This cat’s fur is very soft, dense, coarse to the touch, wavy and so curly that the coat looks like that of a sheep’s fleece. Even its facial and supraorbital vibrissae are curled. Devon Rex This cat’s coat is due to a recessive gene called re (Fig. 5). All three hair types are present but deeply modified. The coat is less wavy and curly than that of the Cornish and in general its coat has a more sparse appearance. The facial and supraorbital vibrissae may be broken or even absent. The r and re genes are recessive mutant Coat Color Genetics 35 VetBooks.ir Fig. 5 Devon Rex cat genes located on different loci of the chromosome, and by crossing a Cornish Rex with a Devon Rex one can obtain non-rex coated kittens. There are other modifications regarding the r genes, especially those of the Oregon Rex, a cat with a coat deriving from the presence of the ro gene, a recessive mutant allele that causes the protection hair to disappear. The coat of the German Rex is caused by the presence of the r gene, identical to that of the Cornish. In the Dutch Rex and in the Selkirk Rex, instead, the genes are two dominant mutant alleles: Rd and Rs, respectively. The Dutch Rex is currently not being bred. The Selkirk rex has a thick, plush and curly coat which can be short or long. 36 M. C. Crosta VetBooks.ir h genes Sphynx/Bambino/Elf/Dwelf The Sphynx is a cat that has no protection or intermediate hairs due to the presence of the recessive hr gene. The sparse underhair, that can even be totally absent, is located on the muzzle, on the outside base of the ears, on the feet, scrotum and tail. The skin is very soft to the touch, resembling suede, and wrinkles are present on the face, between the pinnae and on the shoulders. The cat is medium size, muscular, with wide chest and rounded abdomen. The cross-breeding of the Sphynx with other breeds has resulted in the Bambino, Elf and Dwelf breeds. The Bambino cat is the result of the cross between the Sphynx and the Munchkin (‘Sausage cat’), a short-legged cat. The Bambino is a smaller version of the Sphynx has no hair, a long chest and a rounded abdomen. The hind legs are longer than the front legs, the muzzle is triangular with wide and tall pinnae. The cross between the Sphynx and the American Curl has generated the Elf breed, a naked, tall and muscular cat with prominent cheek bones, like the Sphynx cat. This cat also presents curled pinnae, like the American Curl breed. The breeding of the Elf with the Munchkin/Bambino has given rise to the Dwelf breed (the name is a blend of ‘dwarf’ and ‘elf’, the mythical creature with pointed ears). This cat is small, naked, short-legged and has curled pinnae like the Elf cat. Hrbd genes Donskoy/Peterbald/Levkoy This group includes the Donskoy (Don Sphynx), the Peterbald and the Levkoy. The gene responsible for these breeds is Hrbd, a dominant gene located on a locus different from that of the hr gene. The Donskoy is a middle-sized cat with cuneiform head, wide ears with rounded tips positioned high on the head and medium to long legs. The Donskoy cat is preferable naked; however it occasionally may have hairs called ‘flock’ when less than 2 millimetres long and ‘brush’ when more than 2 millimetres long. The hair is sparse and hard all over the body, with naked areas on the head, upper neck or on the back. These cats, with residual hair, cannot participate in cat shows but are successfully employed for reproduction. The Peterbald derives from the cross of the Don Sphynx with the Siamese/Oriental Shorthair. It has all the morphologic features of the Siamese/Oriental Shorthair (long, elegant and slender body with long legs) but carries all the cutaneous features of the Donskoy, with wrinkles on the face, between the ears and on the shoulder. As for the Donskoy, the naked cats are preferred, but ‘haired’ cats can be used for reproduction. The Levkoy comes from the cross between the Donskoy and the Scottish Fold. The Levkoy may be naked or have residual hair and its pinnae are folded forward like the ones of the Scottish Fold. Again, the naked ones are preferred, but kittens and younger cats can sometimes present some residual hair. Crossing between these breeds and the Sphynx is not allowed. Coat Color Genetics 37 VetBooks.ir Wh Genes Wirehair This group includes a cat breed that has a very particular coat, the American Wirehair, which owes its coat to the dominant mutant gene Wh. All three hair types are present but they appear modified and curly, which makes the Wirehair’s coat hard and coarse to the touch. The Genes Controlling Coat Coloration and Patterns Tabby The transmission of cat coat colours follows precise genetic rules according to Mendel’s laws. If when speaking of hair length the shorthair is the original coat, when speaking of colour patterns all cat coats derive from the tabby. The tabby coat is the most commonly found in nature because it is highly mimetic. Indeed, tabby is the original wild coat, the primordial coloration from which all other coat colours have descended by mutation. The name ‘tabby’ derives from ‘Attabi’, the characteristic Baghdad district famous for making the precious striped silk cloth called ‘taffetà’. This name, later shortened to ‘tabby’, was then used to describe the striped coat of cats. In tabby cats, the stripes seem drawn against the coat’s background that is commonly called Agouti. Agouti and Non-agouti Agouti is an Indian word used to indicate a rodent that lives in the rain forests of Central and South America, subsequently used in genetics to describe the wild coloration of the hare and rabbit. Agouti (A) in the genotype determines a ‘striped’ or ‘banded’ coloration of the coat via a pigment synthesis system called on-off. Darker colour bands produced during the on phase alternate with lighter colour bands produced during the off phase. In this way, each single hair is not of a single colour but is marked by alternated dark and light colour bands and has a dark-coloured tip (Fig. 6). Its recessive mutant allele, non-agouti, represented by the symbol a, suppresses the light-color banding, which is substituted by a dark colored band different from the first one. The hair appears to the eye as self-coloured (solid) because the bands cannnot be distinguished. The difference between a tabby coat and a “self” (solid) coat is well represented by the coat of the leopard and the black panther. As many will know, the leopard and the black panther are the same animal. However, in the leopard the black patches are very visible on the yellow coat, while in the black panther the patches are black on a black background and therefore cannot be appreciated. The non-agouti gene manages to make the light colour bands disappear only with eumelanic colours, but has no effect on pheomelanic colours (in practice, a red non-agouti cat has a striped coat). Agouti allows the striping coat to appear, which means that what one sees in a striped coat is a complex coloration deriving from two colour components and controlled by two different gene groups: Agouti + Tabby. 38 M. C. Crosta VetBooks.ir Fig. 6 Agouti hair coat Gene A not only affects coat coloration but also that of the skin and nose. In eumelanic cats, the nose leather is not one solid colour, like in solid coloured cats, but rather brick red/pink/old rose coloured, rimmed with the coat’s basic colour. Patterns Agouti is the basic colour, i.e. the background on which the pattern seems to be drawn. There are four main patterns associated with the three tabby genes: –– –– –– –– Ticked tabby or Abyssinian Spotted tabby Mackerel tabby Blotched tabby The tabby genes are T, Ta and tb, and they are autosomic (three different alleles on the same locus). They are capable of generating striped coat patterns that are called markings: –– –– –– –– Ta is responsible for the ticked tabby coat (or Abyssinian coat). T is responsible for the mackerel tabby and for the spotted tabby coat. tbtb is responsible for the Blotched tabby or classic tabby coat. Ta is considered dominant over T, T is dominant over tb, and tb is recessive to both. These coats in heterozygous specimens (such as Ttb or TaT) are not as well defined and precise as homozygous coats (TaTa or TT). T is responsible for both the mackerel and the spotted tabby patterns. There are many theories to explain this. Some claim that the spotted coat is derived from a polygenic action; others state it derives from the presence of other genes capable of breaking up and rounding the stripes of mackerel coats. icked Tabby or Abyssinian (Ta Gene) T In this coat, the Agouti is distributed all over the coat and for this reason all of the coat appears evenly ‘ticked’. Each hair has regularly alternating bands of different VetBooks.ir Coat Color Genetics 39 colour (Fig. 7). The root is apricot colour while the tip is of the so-called basic colour, that can be black, chocolate, blue, cinnamon or fawn. The more bands on the hair, the more appreciated the coat. This colour is most frequent in the cats of the savannah and in wild cats living in arid and desert areas, while in selected breeds it is typical of the Abyssinian, of the Singapura and of the Ceylon cat. In some breeds, the presence of stripes on legs, neck, muzzle and tail are considered defects, as in the Abyssinian, while in others they are indispensable, as in the Singapura. ackerel Tabby (T Gene) M Mackerel is the term used to indicate the tabby coat with uninterrupted vertical lines (Fig. 8). ‘Mackerel’ is a fish that has thin parallel stripes that descend from its back to its midline. The cat’s coat has a straight and uninterrupted black line along the spine, Fig. 7 Abyssinian cat Fig. 8 Mackerel tabby cat VetBooks.ir 40 M. C. Crosta running from the back of the head to the base of the tail. On its sides, shoulders and thighs, there are distinct narrow, continuous and parallel stripes. Its legs, tail and neck are well banded. These cats have an ‘M’ on their forehead and two or three lines that follow the profile of the cheeks. They have many small spots on their underside, from the throat to the belly. The ‘M’ on the forehead has inspired quite a few legends. One tells of the baby Jesus trembling in the manger despite being wrapped in blankets. Mary called in all the animals to warm Him but Jesus still trembled. Then a tabby cat appeared and snuggled up to Him in the manger, covered Him with his body and warmed Him. As a sign of her gratitude, Mary drew an M on its forehead. Another legend states that a snake crawled into the sleeve of the Prophet Mohammed’s robe, and a tabby cat killed it immediately. From that moment onwards, all tabby cats were born with the M on their forehead to remind everyone that these cats deserve respect. potted Tabby (T Gene) S The cat with a spotted coat has many small round or oval spots on its coat, separated one from the other and evenly distributed (Fig. 9). A thin, straight and uninterrupted Fig. 9 Spotted tabby cat VetBooks.ir Coat Color Genetics 41 black line may be present from the back of the head to the base of the tail. An M is designed on the forehead and two or three lines follow the profile of the cheeks. The neck shows two uninterrupted stripes, while the legs and tail are banded. They have many small dots on their abdomen, from the neck to the belly. This coat is also called ‘maculate’ and is typical of the Egyptian Mau and of the Ocicat. The ‘resetting’ on the coat of the Bengal can be considered a modified spotted trait. lotched Tabby (tb Gene) B Also known as classic tabby. This is the showiest and most spectacular of coats because the Agouti background is marked by a butterfly-shaped pattern, the upper and lower wings of which are clearly designed on the flanks and shoulders of the cat (Fig. 10). Along the spine, from the back of the head to the base of the tail, there are three large stripes, a central one flanked by another two, distinctly separated and parallel to the first. The forehead bears an M and two or three lines follow the profile of the cheeks. The neck is decorated by two uninterrupted stripes while the legs and tail are banded. They have many small spots on their abdomen, from the neck to the belly. The coat of the Marbled Bengal is considered a classic tabby modified. ifferences Between Tabby and Self-Coloured D • Nose: in self-coloured cats, the colour of the nose is solid. In tabby cats, the nose colour is brick red, pink, old rose, and rimmed with the coat’s basic colour. • Chin: in tabby cats, the colour of the chin is lighter than in self cats. Fig. 10 Blotched tabby cat VetBooks.ir 42 M. C. Crosta • Eyes: the eyes of tabby cats are rimmed with the coat’s basic colour (and sometimes the lips are too) and a halo of lighter colour immediately around the eye. • Ears: in self-coloured cats, the whole ear is evenly coloured, while in the tabby, and especially in tabby Points, a ‘thumbmark’ (or pouce) is present, i.e. a lighter area of colour on the external base of the ear. Self or Solid Colours The original colour is the tabby coat due to the association of the Agouti gene with the tabby alleles. All that was needed was the mutation of the Agouti gene (A) into non-agouti (a) to make the grey-yellowish bands on every single hair to disappear and generate the solid colour coat. Non-tabby cats, usually called self or solid, are cats that have coat of a single colour with hair that is evenly coloured from the root to the tip. The colour of each single hair is defined by the colour genes. Gene B is the colour-coding gene that allows melanosomes to produce eumelanin granules that give the hair a dark coloration. Gene B produces the hair’s black pigmentation. Gene B has two recessive mutant alleles called b (brown or chocolate) and bl (light brown or cinnamon). In these mutations, the pigment granules become deformed until they take on oval (b) or even more elongated (bl) shapes. The granules deformed in this way reflect the light, giving the hair a lighter colour: b produces the colour chocolate while bl the colour cinnamon. Black, B, is the dominant shape, while b and bl are both recessive to gene B, and bl is recessive to b (B > b > bl). Dilution These colours exist in the dilute form. In fact, thanks to the action of the dilution gene also known as the Maltese gene (d), the pigment granules inside the cortex aggregate and take on a different distribution. By doing this, they reflect the light and the coat appears of a lighter colour, allowing black to become blue, chocolate to become lilac and cinnamon to become fawn. Solid coat colours thus are six: Non-diluted Black Chocolate Cinnamon Diluted Blue Lilac Fawn Black The hair should be black from the root up and not contain any traces of brown or have any white hairs or grey underhair. Often the hair tips when exposed to the sun, VetBooks.ir Coat Color Genetics 43 or the collar that is easily soiled by food and water, tend to become reddish or brown coloured. Nose leather and paw pads are black (Fig. 11). Blue The coat that ranges from a very light grey colour to slate grey is called blue. The most desirable is the lighter colour, as even as possible, from the tip to the root, without black tips or white hairs. Nose leather and paw pads should be blue. It is a dilution of black (Fig. 11). Chocolate The coat is milk chocolate coloured with a warm and even hue from the tip to the root of the hairs, without stripes or hairs of other colours. The nose leather is milk chocolate coloured, while the paw pads range from milk chocolate to cinnamon rose. Chocolate is a mutation of black (Fig. 12). Lilac Also called lavender or frost, lilac is a dilution of chocolate. The coat appears evenly pinkish-light grey without any kind of striping (Fig. 13). Nose leather and paw pads are coloured pinkish lavender. Cinnamon The brown coat is very light: this is a mutation of black (Fig. 14). In the Abyssinian and in the Somali, this colour is called sorrel. awn F It is a dilution of cinnamon (Fig. 15). Red and Tortoiseshell Gene O transforms colour pigments into pheomelanin and deactivates the eumelanin production loci. Pheomelanins are granules that produce a red/orange colour. The orange gene is located on the X chromosome and for this reason is defined ‘sex-linked’. Pheomelanic colours do not express all of the changes in hues seen Fig. 11 Black and blue kittens 44 VetBooks.ir Fig. 12 Chocolate cat Fig. 13 Lilac cat M. C. Crosta Coat Color Genetics 45 VetBooks.ir Fig. 14 Cinnamon cat Fig. 15 Fawn cat with eumelanic colours, but only the colours red and cream. The cream colour is obtained through the intervention of dilution genes. There is a very special coat colour known as ‘tortoiseshell’. In this coat, the colours red and black are perfectly mixed or are present as clearly separated and defined patches of colour. Cats displaying this coloration are usually female. As we know, the cat has 38 chromosomes: 36 autosomal and 2 sexual chromosomes. The male is xy and the female xx. Only chromosome x carries colour; y doesn’t. This means the male can be xOy red or xoy non-red (i.e. black). The female can be: –– xOxO red (if both x’s carry orange) –– xOxo tortoiseshell (if one x carries orange and the other x doesn’t) –– xoxo black (if both x’s do not carry orange) The combination xOxo is the only instance (due to the presence of the double x) in which black and red can appear together. Tortoiseshell female cats can be black (or another eumelanic colour) and red or can appear together with white (Fig. 16). When the white is present, the red and VetBooks.ir 46 M. C. Crosta Fig. 16 Diluted tortoiseshell with white kitten black are confined into clearly defined and separate patches of colour. The females that have this particular coat are called tricolour or calico, the North American term. In presence of the dilution gene, black becomes blue and red becomes cream, giving rise to the blue-cream coat and, if white is present, to diluted tortoiseshell and white or diluted calico. In presence of Agouti (A), in the eumelanic areas the tabby pattern will appear. The term ‘calico’ derives from the Indian city of Calicut, in the Kerala region, that was a famous port in the sixteenth century thanks to the flourishing trade between Europe and India. In that city a raw cotton cloth called calico was also made, that was bleached and then dyed with vibrant colours. This term was later used in the United States to indicate multi-coloured objects. The distribution and percentage of colour is defined during the development stage of the embryo. Coats with grey or white underhair or with tabby stripes on the muzzle or in the red spots are not allowed. Alongside the classic black-red combination there is also the chocolate-cinnamon with red. All of these varieties are admitted with tabby markings (stripes). In the United States, the tortoiseshell or blue and cream tabby is also called patched tabby or torbie. Tortoiseshell cats are only females. Should this coat appear in a male specimen, the cat is almost always sterile. Red Red is the definition of the coat that has a magnificent golden-red, warm, pure coloration, evenly distributed from the root to the tip of the hair (Fig. 17). The standard defines it without any tabby markings (stripes) or lighter spotting. The Coat Color Genetics 47 VetBooks.ir Fig. 17 Red and cream tabby cats perfect red self (solid colour) is difficult to obtain because the non-agouti gene (a) that masks the stripes does not have a clean action on pheomelanic colours, as it does on eumelanic colours. For this reason, sometimes residual marking is visible on the head and legs, or, in the attempt to eliminate the stripes, coats of a much too light or washed-out red are obtained. Red self cats without stripes are obtained only by means of very careful selection. Nose leather and paw pads should be brick red. Cream In presence of dilution genes, red becomes a very soft and delicate pastel cream (Fig. 17). The colour is evenly distributed from the root to the tip of the hair and should be as light and homogeneous as possible, without any tabby markings (stripes), shadowing, light-coloured underhair or darker, pointed areas. Blue-Cream In this tortoiseshell cat, the dilution genes soften black into blue and red into cream (Fig. 16). The colours are perfectly mixed and well distributed, even on the extremities, to create a very light mixture with pastel hues. Like the tortoiseshell, the blue- cream cat is only female. Siamese Pattern In genetics, when speaking of the Siamese one speaks of coloured points. In fact, this particular coloration of the extremities is found in many breeds: Siamese, Thai, Persian (colourpoint) (Fig. 18), Sacred Cat of Birman, Ragdoll, Devon Rex and Cornish Rex (Si-rex). The gene involved is the one that regulates the intensity of body colour, i.e. gene C and its mutant alleles called albino alleles. These alleles are all identified using letter c because they are found on the same locus (lower case because c is recessive to C, the gene responsible for coat colour intensity). They all have different suffixes that are the initials of the breeds in which their action plays a primary role. 48 M. C. Crosta VetBooks.ir Fig. 18 Colourpoint cat • • • • • C full colour cb Burmese cs Siamese ca Blue-eyed Albino c Pink-eyed Albino All of the alleles of this group are recessive to C but not among themselves; in fact, between cb (Burmese) and cs (Siamese) there is an incomplete dominance phenomenon. By crossing a Siamese (with light-coloured body and dark tips) with a Burmese (with shadows of colour, darker on the legs and lighter on the body), one obtains a Tonkinese (Fig. 19). The Tonkinese shows intermediate features: intensely coloured tips and body hair which is darker than the Siamese but lighter than the Burmese. Both (cb and cs), however, are dominant over ca (responsible for the Blue-eyed Albino), that in turn is dominant over c (Pink-eyed Albino) (C > cs and cb cs > ca > c). cb Burmese Albino alleles work by progressively decreasing the pigmentation of the eyes and hair. In the Burmese, because of the cb gene, black (C) becomes seal (sable or dark sepia) and the eyes, that are partially depigmented by the gene, tend towards yellow (Fig. 20). cs Siamese In the Siamese, the gene cs causes the seal colour to be limited only to the extremities (mask, ears, legs, feet and tail) while the rest of the body is coloured anywhere from beige to magnolia white. The eyes are deep blue. Coat Color Genetics 49 VetBooks.ir Fig. 19 Tonkinese cat Fig. 20 Burmese cat c a Blue-Eyed Albino In the Albino with blue eyes, the lack of pigmentation results in white hair and very pale blue eyes. c Pink-Eyed Albino In the Albino with pink eyes, caused by the presence of the c gene, in addition to the total lack of pigmentation, the eyes are pink because the iris is transparent and the retina’s blood vessels become visible. VetBooks.ir 50 M. C. Crosta The Siamese gene causes the mutation of the structural gene of the tyrosinase enzyme, making it especially temperature-sensitive. An increase in temperature, in fact, deactivates it, and this is why on the body, that is warmer, there is a decrease in pigmentation (and therefore the coat is paler in colour). At the extremities, that are cooler, there is a larger deposit of pigment that creates the darker ‘point’ effect. Point kittens are born white because in the uterus the temperature is higher and more constant (38.5 °C), and their colourpoints start showing only a few days after birth. Climate changes can affect coat coloration too. In fact, cats living in warm climates are lighter coloured than those that live in cold climates. The colourpoint in Siamese cats regulates the colour of their body coat: the darker the points, the darker the rest of the coat (a seal point will have a darker coat compared to a red point). The coat also darkens with age. For this reason, Siamese cats have a rather short showing career, because the judges prefer more highly contrasting coats. The Siamese pattern may appear in other cat breeds, such as the Sacred Cat of Birman, the Devon Rex, the Cornish Rex and others. White Spotting Coats with white spots or patches are quite common in nature. The white spots on a cat’s coat are genetically determined by the S (white spotting) gene and are transmitted as independent entities. This explains why white spotting can be associated with any basic coat colour. Cats with white spotting are called bicolour and tricolour, and it is common to add ‘and white’ to the cat’s colour name. In this way, a black cat with white spots becomes ‘black and white’, a red blotched tabby becomes a ‘red blotched tabby and white’, while the tortoiseshell and white cat is more simply called ‘tricolour’ or ‘calico’. The S gene prevents coat coloration because it does not allow the melanin granules to settle in the follicles from which the hairs grow. As the W gene (responsible for the total depigmentation of the hair), S is a dominant epistatic gene but, unlike W, S does not affect the whole coat but just some patches of it, and its expression is enhanced by modifier polygenes that can amplify its action. The white spots show up more intensely if the S is homozygous (SS) compared to its heterozygous state (Ss). For this reason, it is quite common to see cats with just a few tufts of white hair on the chest and belly, or the extreme opposite whereby the coats are almost totally white with colour being limited to just a few areas of the head, back and tail. In fact, due to the variability of these coats, it is thought that there are various genes (or polygenes) conditioning the expression of the S gene. The formation of more extensive white areas confines colour into more distinct and visible spots. In tricolour coats, the spots of red and black are larger when the proportion of white is higher. Just like the W gene, the S gene seems to be linked to congenital deafness. It is possible for a white spotted cat to have deafness in the ear above the blue eye. White spotted coats are classified according to the percentage of white they contain. VetBooks.ir Coat Color Genetics 51 Mitted The small amount of white (1/4) is limited to the four feet. A white spot is preferred on the nose and/or between the eyes, while a white line should be present on the lower part of the body, starting from the throat and ending at the base of the tail. This coat is typically found in the Ragdoll. Bicolour This category includes coats that have a ratio of 2/3 colour to 1/3 white. Colour should be present on the muzzle (where an upturned ‘V’ is desirable), on the spine, head, tail and external area of the legs. White is desirable on the chest, belly and the inside area of the legs (Fig. 21). Also preferable is a white spot on the back, but its absence is not a penalty. This category allows for coats that show up to 50% white and 50% colour. Especially appreciated are specimens with a white ‘flame’ on their muzzle. Harlequin This coat has a much higher grade of white spotting compared to colour. Solid colour, in fact, covers only 1/6 of the coat and is limited to the top of the head, tail Fig. 21 Bicolour cat 52 M. C. Crosta VetBooks.ir Fig. 22 Harlequin cat and legs. Three or four clearly marked and separate colour spots are desirable on the back (Fig. 22). Colour spotting is random, but in any case, if located on the back, the spots cannot be fewer than four. A white flame on the muzzle is highly desirable. an V This category includes coats with colour markings on the head and tail. On the head, the colour is preferably confined to two large spots separated by a white line between the ears, while the tail should be evenly coloured down to the base. Not more than three colour spots on the body are accepted. Coats with more than three colour spots are considered to be Harlequin. The rest of the body is all-white. This name has been derived from the Turkish Van, the cat breed that features this coat. acred Cat of Birman S This cat’s coat is long-haired, colourpointed and features white ‘gloves’. The white- gloved paws of this cat is the breed’s signature feature, although this peculiar distribution of regular and symmetrical white spots on the four feet has divided genetists and scholars. Some authors claim that its genotype is similar to that of the colourpoint (cscsll) but with the addition of the S gene (Piebald White Spotting gene). According to them, the expression of S is conditioned by modifier polygenes that allow white spots to follow a precise distribution on the four feet. Other authors VetBooks.ir Coat Color Genetics 53 instead describe the presence of g (gloves), a recessive autosomic gene that in double dose is capable of confining the white spotting to the extremities. The latter hypothesis now seems to be the most credited, although it is not precisely understood whether g can be considered a second gene totally different and independent from S, but capable of changing the expression of the latter (in this case, it would seem likely that there is a Ssgg genotype in which S codes for spotting and g codes for the white spotting’s positioning on the feet) or whether it is an allele found on the same locus as S. Yet others believe that it is a dominant gene with incomplete penetrance and totally different from S. Dominant White White is not a colour but an absence of colour, coded by the dominant, epistatic gene W. This gene is responsible for the complete depigmentation of the hair (Fig. 23). It masks the expression of all other colours (epistasis), including white Fig. 23 White cat VetBooks.ir 54 M. C. Crosta spotting and Siamese colourpoint, which means that a white cat can be defined as a cat of any colour painted white. The progeny of a homozygous white cat will be entirely white; on the contrary, a heterozygous white cat crossed with a non-white cat can generate coloured kittens as well. By examining the non-white progeny of such a cat, one can discover its hidden colour. If one crosses a white male cat with a red female cat, for example, and this cross produces a tortoiseshell kitten, then the hidden colour of the male cat will be black. Sometimes the epistatic effect of this gene is not absolute. Often, a small spot remains visible on white kittens’ heads, but disappears by adulthood. The W gene is unfortunately often associated with deafness, because it codes for a degeneration of the cochlea in the ear and atrophy of the organ of Corti. This genetic defect is congenital and irreversible. The white Oriental, also known as Foreign White, has the cs gene (Siamese) and the W gene (white), and therefore is a Siamese with the W gene (cscsW-) and not an albino Siamese from which it differs both by genotype and by phenotype. Silver Coats Cats with silver coats (smoke, shaded, Chinchilla and silver tabby) are perhaps the most striking and fascinating of them all. In all of these coats, only the tip of the hair is coloured, while the root section is white. All of these cats share the ‘colour inhibitor’ gene I that prevents the development of pigment in the hair and suppresses its yellow-greyish banding, which results in a silver coloration effect. Each single hair of these cats is coloured to varying degrees only at the tip, that can be of any colour: black, blue, red, tortoiseshell and so on, while the base, closest to the skin, is white. Even the skin remains normally pigmented. There are many theories regarding the genesis of silver coats. Until not long ago, the most widely accepted theory was based on a single gene responsible for this ‘non-pigmentation’, i.e. a mutation of the colour inhibitor gene I, a dominant autosomic gene that prevents pigment development in the hair (not to be confused with the Albino alleles) probably by limiting the quantity of pigment destined to the growing hair. The I gene suppresses the yellow- greyish bands of the tabby hair and at the same time codes for a pale silver colour at the base of the hair. In order to differentiate between silver tabby, Chinchilla and silver shaded, this theory envisaged the intervention of modifier polygenes capable of regulating the intensity of the I gene and therefore the different proportions between quantity of coloured hair and silver hair. Other authors have proposed the presence of another gene, Ch, different and independent from I. This theory, called the ‘two genes theory’, is based on the assumption that the I gene erases the yellow-greyish bands and the Ch gene, dominant but independent from I, suppresses ticking and relegates it to the tip of the hair shaft (tipping). The most recent theory proposes yet another solution to explain the many questions that arise when analysing the various coats. The presence of the I gene – colour inhibitor – is confirmed as regards the depigmentation and silver-colouring VetBooks.ir Coat Color Genetics 55 of the hair’s base while, to justify the various widths of the underhair, several polygenes, called Widebanding Genes Wb (undercoat width genes), have been called into play. The polygenes are capable of regulating band width close to the base and act in varying degrees (low, medium, high) causing the widening of the pale band in the Agouti coat. To explain the tipping of the Chinchilla coat, another recessive gene, the superwide band gene (swb), is assumed to combine with I and with Wb. This is the most widely accepted theory at the moment, but due to the complexity of the matter and to the many issues still to be cleared up, one continues to classify silver coats based on the varying silver to coloured hair ratio. Accordingly, based on the width of the coloured part of the hair shaft, called tipping, the following coats are distinguished. Smoke The Smoke is also known as the ‘cat of contrast’ because it has only a very small white band at the base of the hair in contrast with the very wide band of coloured tipping. The silver base should be evenly distributed all over the body, head legs and tail included (Fig. 24). The tipping (from the tip to midway down the hair shaft) is usually black but can also be blue, red or tortoiseshell. In longhair cats, the contrast is even more evident. A Smoke Persian, for example, looks entirely black but the contrast becomes clearly apparent as soon as it moves or when patted. Shaded This coat type has tipping (coloured part of the hair shaft) on about 1/3 of the hair (Fig. 25). The tipping can extend to the muzzle, legs and on the heel and results in a slightly darker colouring overall compared to the Chinchilla. The coat should not show tabby markings, dark spots or cream hues. The nose leather is brick red rimmed with a thin black line. The tips can be of various colours, the most common being black, although the variations of blue, chocolate, lilac and tortoiseshell are also admitted. Fig. 24 Smoke coat 56 M. C. Crosta VetBooks.ir Fig. 25 Shaded cat Fig. 26 Chinchilla cat Chinchilla The appearance of the Chinchilla (also called ‘Shell’) is that of a cat with only light silver tipping and a white underhair. The tipping involves about 1/8 of the hair (Fig. 26). The chin, chest, belly, inside of the thighs, the underside of the tail and the hock should be pure white. The head, ears, back, flanks, legs and tail are slightly shaded due to the presence of the tipping. Silver-shaded and Chinchilla coats are genetically identical, and can be found together in the same litter. When the polygenes have an intense action, the result is a Chinchilla, and when the action is bland the result is a silver shaded. Sometimes it is not easy to distinguish them. When in doubt, the colour of the heels will give the answer: silver heels mean silver shaded (Fig. 27), pure white heels mean Chinchilla (Fig. 28). VetBooks.ir Coat Color Genetics 57 Fig. 27 Heels of Chinchilla cat (lighter color) Silver Tabby This is simply a tabby cat in which the I gene has erased the yellow-greyish bands, giving place to the white-silver hair to strikingly contrast with the striping above (Fig. 29). Cameo The base of the coat is silver and the tipping is red. Based on the length of the tipping, the cat coats are defined as Smoke Cameo, Shaded Cameo and Shell Cameo. Golden This is a special colouring of the coat having a warm apricot coloured underhair and black tipping. The Golden has the Agouti (A) gene, absence of the I gene (being ii) and the contemporary presence of wideband polygenes Wb. The genes described in this chapter are summarized in Table 1. 58 VetBooks.ir Fig. 28 Heels of silver shaded cat (darker color) Fig. 29 Silver tabby cat M. C. Crosta Coat Color Genetics 59 VetBooks.ir The Vibrissae The Vibrissae, commonly called ‘whiskers’, are very special hairs (Fig. 30). Almost three times larger and stiffer than normal hairs, they are located three times deeper into the dermis. They have a sheath of connective tissue rich in elastic fibres and they are served by a rich array of nerves and blood vessels. In addition to being found on the cat’s cheeks on the sides of the mouth (12 on each side, in orderly rows), they are also located above the orbits as well as on the legs at the carpal level. Whiskers move constantly and stimulate the receptors of the nerve endings. For this reason, they constitute a powerful information system for monitoring the cat’s immediate surroundings. These highly specialised receptors use afferent neurons to transmit signals to the trigeminal nerve ganglion, and from there to the part of cerebral cortex in charge of perceiving the somatic-sensorial stimuli, the minimal and almost imperceptible changes in the stimulated vibrissae, as well as all of the highly precise information regarding the extent, direction and duration of this change in status. Fig. 30 Vibrissae 60 VetBooks.ir Fig. 31 White cat. The W gene (dominant white) masks the expression of all of the other genes responsible for coloration and colour distribution Fig. 32 Tabby cat. All cats are genetically tabby and possess striping in their genotype Fig. 33 Orange cats (O gene) M. C. Crosta VetBooks.ir Coat Color Genetics Fig. 34 Tabby kittens. Agouti is the background colour against which one sees the stripes of a tabby coat Fig. 35 Siamese cat (cs gene) 61 VetBooks.ir 62 M. C. Crosta The position of the vibrissae changes in function of the animal’s activity and mood: when the cat attacks or is in a position of defence, it will point the vibrissae towards the rear. The vigil cat, focused on perceiving every single signal, points them forwards. When instead they are curved forwards and pointing down towards the ground, they are being used to recognize the ground and are ready to reveal any pit-holes or other types of unevenness. The vibrissae pointed forwards to almost embrace the captured victim are being used to give the exact position of the prey and the direction of its fur or feathers so that the cat can understand from which end it must swallow it. Vibrissae also play an important role in defending a cat’s eyes, because they function like eyelashes. It is enough to touch them lightly and the eyelids will close immediately. This proves highly useful when hunting, because in its predatory state the cat is concentrated on the prey, has its pupils totally dilated by adrenalin and therefore finds it difficult to focus on objects that are very close, such as small branches, bushes, grass or any other obstacle nearby. Because they just outpast its face, the vibrissae touch these obstacles first and cause the eyelids to close and defend the eyes. The tactile functions of the vibrissae have been widely studied and debated. The vibrissae can act as airflow sensors. They are allegedly capable of detecting – and therefore of informing the cat about – the smallest vortices of air returned by the objects it encounters or the weaker air currents created when the air impacts an obstacle. This makes it easy for the cat to move and change position in the dark of night without bumping into objects. Only such a precise and perfect mechanism can explain the cat’s incredible skill and precision when hunting at night: with its vibrissae, the cat can acquire an instantaneous and precise perception of its prey and capture it. This happens in blind cats too. A blind or partially sighted cat moves its head from one side to the other to perceive the ground’s asperities and any obstacles with its vibrissae. The blind cat lacking vibrissae instead is highly deficient in this respect. General References 1. Adalsteinnson S. Establishment of equilibrium for the dominant lethal gene for Manx taillessness in cats. Theor Appl Genet. 1980;58:49–53. 2. Affections héréditaires et congénitales des carnivores domestiques, Le point vétérinaire vol 28 N° spécial 1996. 3. Alhaidari Z, Von Tscharner C. Anatomie et physiologie du follicule, pileux chez les carnivores domestique. Prat Med Chir Anim Comp. 1997;32:181. 4. Alhaidari Z, Olivry T, Ortonne J. Melanocytogenesis and melanogenesis: genetic regulation and comparative clinical diseases. Vet Dermatol. 1999;7:10. 5. Anderson RE, et al. Plasma lipid abnormalities in the Abyssinian cat with a hereditary rod-cone degeneration. Exp Eye Res. 1991;53(3):415–7. 6. Baker HJ, Lindsey JR. Feline GM1 gangliosidosis. Am J Pathol. 1974;74:649–52. 7. Barnett KC, Gurger IH. Autosomal dominant progressive retinal atrophy in Abissinian cats. J Hered. 1985;76:168–70. 8. Bellhorn RW, Fischer CA. Feline central retinal degeneration. J Am Vet Med Assoc. 1970;157:842–9. VetBooks.ir Coat Color Genetics 63 9. Bergsma DR, Brown KS. White fur, blue eyes and deafness in the domestic cat. J Hered. 1971;62:171–85. 10. Biller DS, et al. Polycystyc kidney disease in a family of Persian cats. J Am Vet Med Assoc. 1990;196:1288–90. 11. Bistner ST. Hereditary corneal distrophy in the Manx cat: a preliminary report. Investig Ophthalmol. 1976;15:15–26. 12. Bland van den Berg P, et al. A suspected lysosomal storage disease in Abyssinian cats. Genetic and clinical pathological aspects. J S Afr Vet Assoc. 1977;48:195–9. 13. Blaxter A, et al. Periodic muscle weakness in Burmese kittens. Vet Rec. 1986;118(22):619–20. 14. Bosher SK, Hallpike CS. Observations of the histopathological features, development and pathogenesis of the inner ear degeneration of deaf white cats. Proc R Soc Lond B Biol Sci. 1965;162:147–70. 15. Bosher SK, hallpike CS. Observations of the histogenesis of the inner ear degeneration of the deaf white cat. J Laryngol Otol. 1966;80:222–35. 16. Bourdeau P, et al. Alopecie hereditaire generalisee feline. Rec Med Vet. 1988;164:17. 17. Boyce JT, et al. Familial renal amyloidosis in Abyssinian cats. Vet Pathol. 1984;21(1):33–8. 18. Boyce JT, et al. Familial renal amyloidosis in Abyssinian cats. Vet Pathol. 1984;21:33–8. 19. Breton RR, Nancy CJ. Feline genetics. Net Pets; 1999. 20. Bridle KH, et al. Tail tip necrosis in two litters of Birman kittens. J Small Anim Pract. 1998;39(2):88–9. 21. Burditt LJ, et al. Biochemical studies on a case of feline mannosidosis. Biochem J. 1980;189:467–73. 22. Carlisle JL. Feline retinal atrophy. Vet Rec. 1981;108:311. 23. Casal M, et al. Congenital hypothricosis with thimic aplasia in nine Birman kittens. ACVIM abstracts N° 68, Washington, DC; 1993. 24. Centerwall WR, Benirschke K. Male tortoiseshell and calico cats. J Hered. 1973;64:272–8. 25. Chapman VA, Zeiner FN. The anatomy of polydactylism in cats with observations on genetic control. Anat Rec. 1961;141:205–17. 26. Chew DJ, et al. Renal amyloidosis in related Abyssinian cats. J Am Vet Med. Assoc. 1982;181:140–2. 27. Clark RD. Medical, genetic and behavioral aspects of purebred cats. Fairway: Forum publications Inc; 1992. 28. Collier LL, et al. Ocular manifestations of the Chédiak-Higashi syndrome in four species of animals. J Am Vet Med Assoc. 1979;175:587–90. 29. Collier LL, et al. A clinical description of dermatosparaxis in a Himalayan cat. Feline Pract. 1980;10(5):25–36. 30. Cooper ML, Pettigrew JD. The retinophthalamic pathways in Siamese cats. J Comp Neurol. 1979;187:313–48. 31. Cooper ML, Blasdel GG. Regional variation in the representation of the visual field in the visual cortex of the Siamese cat. J Comp Neurol. 1980;193:237–53. 32. Cork LC, et al. The pathology of feline GM2 gangliosidosis. Am J Pathol. 1978;90:723–34. 33. Cork LC, et al. GM2 ganglioside lysosomal storage disease in cats. Science. 1977;196:1014–7. 34. Cotter SM, et al. Hemofilia a in three unrelated cats. J Am Vet Med Assoc. 1978;172:166–8. 35. Counts DF, et al. Dermatosparaxis in a Himalayan cat. Biochemical studies of dermal collagen. J Invest Dermatol. 1980;74:96–9. 36. Creel D, et al. Abnormal retinal projections in cats with Chédiak-Higashi syndrome. Invest Ophthalmol Vis Sci. 1982;23:798–801. 37. Crowell WA, et al. Polycystic renal disease in related cats. J Am Vet Med Assoc. 1979;175:286–28. 38. Danforth CH. Hereditary of polydactyly in the cat. J Hered. 1947;38:107–12. 39. Davies M, Gill I. Congenital patellar luxation in the cat. Vet Rec. 1987;121:474–5. 40. De Maria R, et al. Beta-galactosidase deficiency in a Korat cat: a new form of feline GM1- gangliosidosis. Acta Neuropathol. 1998;96(3):307–14. VetBooks.ir 64 M. C. Crosta 41. DeForest ME, Basrur PK. Malformations and the Manx syndrome in cats. Can Vet J. 1979;20:304–14. 42. Desnick RJ, et al. In: Desnick RJ, et al., editors. Animal models of inherited metabolic diseases. New York: Liss; 1982. p. 27–65. 43. Di Bartola SP, et al. Pedigree analysis of Abyssinian cats with familial amyloidosis. Am J Vet Res. 1986;47:2666–8. 44. Donovan A. Postnatal development of the cat retina. Exp Eye Res. 1966;5:249–54. 45. Ehinger B, et al. Photoreceptor degeneration and loss of immunoreactive GABA in the Abyssinian cat retina. Exp Eye Res. 1991;52(1):17–25. 46. Elverland HH, Mair IWS. Heredity deafness in the cat. An electron microscopic study of the spiral ganglion. Acta Otolaryngol. 1980;90:360–9. 47. Farrell DF, et al. Feline GM1 gangliosidosis: biochemical and ultrastructural comparisons with the disease in man. J Neuropathol Exp Neurol. 1973;32:1–18. 48. Flecknell PA, Gruffydd-Jones TJ. Congenital luxation of the patellae in the cat. Feline Pract. 1979;9(3):18–9. 49. Fraser AS. A note on the growth of the rex and angora cats. J Genet. 1953;51:237–42. 50. Freeman LJ. Ehlers-Danlos syndrome in dogs and cats. Semin Vet Med Surg. 1987;2:221. 51. French TW, et al. A bleeding disorder (von Willebrand’s disease) in a Himalayan cat. J Am Vet Med Assoc. 1987;190:437–9. 52. Gorin MB, et al. Sequence analysis and exclusion of phosducin as the gene for the recessive retinal degeneration of the Abyssinian cat. Biochim Biophys Acta. 1995;1260(3):323–7. 53. Harpster NK. Cardiovascular diseases of the domestic cat. Adv Vet Sci Comp Med. 1977;21:39–74. 54. Haskins ME, et al. In: Desnick RH, editor. Animal models of inherited metabolic diseases. New York: Liss; 1982. p. 177–201. 55. Hearing JV. Biochemical control of melanogens and melanosomal organization. J Investig Dermatol Symp Proc. 1999;4:24–8. 56. Hendy-Ibbs PM. Hairless cats in Great Britain. J Hered. 1984;75:506–7. 57. Hendy-Ibbs PM. Familial feline epibulbar dermoids. Vet Rec. 1985;116:13–4. 58. Hirsch VM, Cunningham JA. Hereditary anomaly of neutrophil granulation in Birman cats. Am J Vet Res. 1984;45:2170–4. 59. Holbrook KA. Dermatosparaxis in a Himalayan cat. Ultrastructural studies of dermal collagen. J Invest Dermatol. 1980;74:100–4. 60. Hoskins JD. Congenital defects of the cat. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. Philadelphia: Saunders; 1995. 61. Howell JM, Siegel PB. Morphologic effects of the Manx factor incats. J Hered. 1966;57:100–4. 62. Jackson OF. Congenital bone lesions in cats with fold-ears. Bull Feline Advis Bur. 1975;14(4):2–4. 63. Jacobson SG, et al. Rhodopsin levels and rod-mediated function in abysinian cats with hereditary retinal degeneration. Exp Eye Res. 1989;49(5):843–52. 64. James CC, et al. Congenital anomalies of the lower spine and spinal cord in Manx cats. J Pathol. 1969;97:269–76. 65. Jezyk PF, et al. Alpha-mannosidosis in a persian cat. J Am Vet Med Assoc. 1986;189:1483–5. 66. Jones BR, et al. Preliminary studies on congenital hypothyroidism in a family of Abyssinian cats. Vet Rec. 1992;131(7):145–8. 67. Johnson CW. The Shaded American Shorthair, 1999 Cat Fanciers’ Association Yearbook, CFA Inc, New Jersey. 68. Koch H, Walder E. A hereditary junctional mechanobullous disease in the cat. Proc World Congr Vet Dermatol. 1992;2:111. 69. Kramer JW, et al. The Chédiak-Higashi syndrome of cats. Lab Investig. 1977;36:554–62. 70. “La guide des chats” Selections du Reader’s Digest, 1992. 71. Leipold HW. Congenital defects of the caudal vertebral column and spinal cord in Manx cats. J Am Vet Med Assoc. 1974;164:520–3. VetBooks.ir Coat Color Genetics 65 72. Loxton H. The noble cat, aristocrat of the animal world. New York: Portland House; 1990. 73. Liu S-K. Pathology of feline heart disease. Vet Clin North Am. 1977;7(2):323–39. 74. Livingston ML. A possible hereditary influence in feline urolithiasis. Vet Med Small Anim Clin. 1965;60:705. 75. Loevy HT. Cytogenic analysis of Siamese cats with cleft palate. J Dent Res. 1974;53:453–6. 76. Loevy HT, Fenyes VL. Spontaneous cleft palate in a family of Siamese cats. Cleft Palate J. 1968;5:57–60. 77. Lomax TD, et al. Tabby pattern alleles of the domestic cat. J Hered. 1988;79(1):21–3. 78. Lorimer. The silver inhibitor gene. Cat Fanciers J. 79. Malik R. Osteochondrodysplasia in Scottish fold cats. Aust Vet J. 1999;77(2):85–92. 80. Martin AH. A congenital defect in the spinal cord of the Manx cat. Vet Pathol. 1971;8:232–9. 81. Mason K. A hereditary disease in the Burmese cats manifested as an episodic weakness with head nodding and neck ventroflexion. J Am Anim Hosp Assoc. 1988;24:147–51. 82. Muldoon LL, et al. Characterization of the molecular defect in a feline model for type-II GM2-gangliosidosis (Sandhoff’s disease). Am J Pathol. 1994;144(5):1109–18. 83. Narfstrom K. Hereditary progressive retinal atrophy in the Abyssinian cat. J Hered. 1983;74:273–6. 84. Narfstrom K, et al. Retinal sensitivity in hereditary retinal degeneration in Abyssinian cats: electrophysiological similarities between man and cat. Br J Ophthalmol. 1989;73(7): 516–21. 85. Neuwelt EA, et al. Characterization of a new model of GM2 gangliosidosis (Sandhoff’s disease) in Korat cats. J Clin Invest. 1985;76(2):482–90. 86. Noden DM, et al. Inherited homeotic midfacial malformations in burmese cats. J Craniofac Genet Dev Biol Suppl. 1986;2:249–66. 87. Paasch H, Zook BC. The pathogenesis of endocardial fibroelastosis in Burmese cats. Lab Investig. 1980;42:197–204. 88. Paradis M, Scott DW. Hereditary primary seborrhea oleosa in Persian cats. Feline Pract. 1990;19:17. 89. Patterson DF, Minor RR. Hereditary fragility and hyperextensibility of the skin of cats. Lab Investig. 1977;37:170–9. 90. Pearson H, et al. Pyloric stenosis and oesophageal dysfunction in the cat. J Small Anim Pract. 1974;15:487–501. 91. Pedersen NC. Feline husbandry. Goleta: American Veterinary Publications Inc; 1991. 92. Prieur DJ, Collier LL. Morphologic basis of inherited coat color dilutions of cats. J Hered. 1981;72:178–82. 93. Prior JE. Luxating patellae in Devon rex cats. Vet Rec. 1985;117(7):154–5. 94. Robinson R. Devon rex: a third rexoid coat mutant in the cat. Genetica. 1969;40:597–9. 95. Robinson R. Expressivity of the Manx gene in cats. J Hered. 1993;84(3):170–2. 96. Robinson R. Genetics for cat breeders. 2nd ed. Oxford: Pergamon Press Ltd; 1987. 97. Robinson R. German rex: a rexoid coat mutant in the cat. Genetica. 1968;39:351–2. 98. Robinson R. The Canadian hairless or Sphinx cat. J Hered. 1973;64:47–8. 99. Robinson R. Oregon rex: a fourth rexoid coat mutant in the cat. Genetica. 1972;43:236–8. 100. Robinson R. The rex mutants of the domestic cat. Genetica. 1971;42:466–8. 101. Rubin LF. Hereditary cataract in Himalayan cats. Feline Pract. 1986;16(4):14–5. 102. Scott DW. Cutaneous asthenia in a cat. Vet Med (SAC). 1974;69:1256. 103. Searle AG, Jude AC. The rex type of coat in the domestic cat. J Genet. 1956;54:506–12. 104. Silson M, Robinson R. Hereditary hydrocephalus in the cat. Vet Rec. 1969;84:477. 105. Simpson J. The white spotting gene: new Zealand Cat Fancy Inc. (NZCF). 106. Sponenberg DP, Graf-Webster E. Hereditary meningoencephalocele in Burmese cats. J Hered. 1986;77:60. 107. Stebbins KE. Polycystyc disease of the kidney and liver in an adult Persian cat. J Comp Pathol. 1989;100(3):327–30. 108. Stephen G. Legacy of the cat. San Francisco: Cronicle Books; 1990. VetBooks.ir 66 M. C. Crosta 109. Turner P, Robinson R. Melaninn inhibitor. A dominant gene in the domestic cat. J Hered. 1980;71:427–8. 110. der Linde V, Sipman JS, et al. Generalized AA-amyloidosis in Siamese and oriental cats. Vet Immunol Immunopathol. 1997;56(1–2):1–10. 111. Wilkinson GT, Kristensen TS. A hair abnormality in Abyssinian cats. J Small Anim Pract. 1989;30:27. 112. Wright M, Walter S. le livre du chat. Paris: Septimus editios; 1982. 113. Zook BC. The comparative pathology of primary endocardial fibroelastosis in Burmese cats. Virchow Arch (Pathol Anat). 1981;390:211–27. 114. Zook BC, et al. Encephalocele and other congenital craniofacial anomalies in burmese cats. Vet Med (SAC). 1983;78:695–701. VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination Andrew H. Sparkes and Chiara Noli Abstract As a naturally solitary species that is both highly territorial and not naturally social, veterinary visits for the cat and the cat owner can be extremely challenging. The fact that the cat has been removed from its home territory (where it feels safe) and brought to the clinic (an unfamiliar environment) means that any cat will naturally experience anxiety, fear, and stress during the visit. For these reasons, it is important that any veterinary visit follows “cat-friendly” principles to ensure stress is minimized. This will help reduce the severity of stress-induced changes in laboratory parameters, facilitate an easier clinical examination, and ensure that owners will be willing to bring their cat back to the clinic when needed. This chapter will deal with how to perform a general and a dermatological examination, including the description of skin lesions and diagnostic procedures, in the feline patient. Introduction As a naturally solitary species that is both highly territorial and not naturally social, veterinary visits for the cat and the cat owner can be extremely challenging. The fact that the cat has been removed from its home territory (where it feels safe) and brought to the clinic (an unfamiliar environment) means that any cat will naturally experience anxiety, fear, and stress during the visit. For these reasons, it is important that any veterinary visit follows “cat-friendly” principles to ensure stress is minimized and anxieties are relieved rather than reinforced. A. H. Sparkes (*) Simply Feline Veterinary Consultancy, Shaftesbury, UK C. Noli Servizi Dermatologici Veterinari, Peveragno, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_3 67 VetBooks.ir 68 A. H. Sparkes and C. Noli Using cat-friendly principles to minimize stress has numerous benefits. Not only does it improve the welfare of the feline patient, it also helps to reduce the severity of stress-induced changes in laboratory parameters, it facilitates an easier clinical examination, it reduces the risk of human injury from fear-induced feline aggression, and helps to ensure that owners will be willing to bring their cat back to the clinic when needed. A more thorough discussion of cat-friendly principles can be found on International Cat Care’s “Cat Friendly Clinic” web site (see www.catfriendlyclinic. org), but some of the important issues are covered here. Before the Cat Arrives For many owners, the process of taking a cat to the clinic is highly traumatic. They will have to catch the cat, confine it in a basket, take it away from its natural environment, often transport it in a car, and then bring it into the clinic. Understanding the implications of veterinary visits for cat owners, and what needs to be done to reduce the negative impact, will help enormously. Advising owners on how best to bring the cat to the clinic and helping them remain calm and relaxed has a very positive effect, both on the owner and the cat. The cat will be exposed to many stressors such as: • • • • • • A strange cat basket An unfamiliar car journey An unfamiliar environment in the clinic Strange odors, sights, and noises on the journey and in the clinic Unfamiliar people and animals, which can be highly threatening Being handled and examined by unfamiliar people Suitable cat carriers should be strong, escape proof, and allow easy access for both the cat, the owner and the clinic staff. Carriers with a large top opening are usually preferred as they allow easy and gentle lifting of the cat in and out of the carrier. The carrier should enable the cat to hide if possible, but if it is open on all sides (e.g., plastic coated wire baskets), then placing a blanket over the carrier to allow the cat to hide is helpful. Plastic carriers that allow the top half to be removed completely can be useful as some cats will feel safer remaining in their carrier during a consultation, and most of a clinical examination can be conducted with the cat in the carrier with the top removed. Ideally, the carrier should be integrated as “part of the furniture” in the cat’s home environment. If it is somewhere the cat choses to rest and sleep in on occasions, or if it is somewhere it is fed frequently, the cat will regard it as part of its territory rather than seeing it as a clue that a stressful journey is ahead, if it only comes out for veterinary visits. Ensuring that some of the cat’s usual bedding is used VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination 69 in the carrier during the visit will also be reassuring to the cat as this will contain the odors the cat associates with its home territory. In addition, the use of synthetic feline facial pheromone spray or wipes in the carrier and/or on the bedding may be helpful. Asking the owner to bring extra bedding is also a good idea in case the cat soils the basket with feces or urine. During a car journey, ensuring the carrier is restrained securely (eg, in a foot well) and will not move during the journey is important. Driving calmly will be helpful and if necessary cover the basket with a blanket to ensure the cat is able to hide. With cats that are known to repeatedly become highly anxious and aroused during a veterinary visit and during the journey to the clinic, consideration can be given to the use of anxiolytic drugs such as gabapentin [1, 2]. While not recommended for routine use, there are undoubtedly some cats that will benefit from such an approach. The Waiting Room A well-designed waiting room with cat-friendly staff is important. The aim should be to create a calm and non-threatening environment for the cat to wait in so that anxiety is reduced rather than heightened. An atmosphere that reassures owners that the clinic is staffed by people who care about both them and their cats will also help to create a positive impression. The waiting room should be designed and used in a way that minimizes the threats cats may feel (visual, aural, olfactory, etc.). Ideally, a clinic would have a separate waiting room for cats, but if this is not possible, consider physically separating the waiting room into two different areas for dogs and cats. Appropriate walls or barriers should be used to ensure visual contact is avoided between dogs and cats (Fig. 1), and measures should be taken to avoid having barking or noisy dogs in the waiting room (e.g., getting noisy dogs to wait outside). Fig. 1 Having a separate waiting area for cats and cat owners that is quiet, and where cats cannot see dogs helps to reduce stress during veterinary visits VetBooks.ir 70 A. H. Sparkes and C. Noli The location and size of the cat waiting area should be appropriate for the clinic, and thought should be given to the route that cats take into and out of it. The cats should encounter minimal human and animal traffic while in the waiting area. The value of a feline-only area is greatly compromised if cats have to pass through a noisy area or pass by dogs to get to the consulting room. Having the cat waiting area adjacent to a cat consulting room can help overcome some of these problems. Other important considerations for the feline waiting area include: • Having a low reception desk, or a wide shelf in front of the reception desk where owners are encouraged to place cat baskets (above the head height of most dogs). This helps to reduce anxiety as cats feel more threatened when at floor level; • Prevent or reduce any noises from the consultation rooms reaching the waiting area; • Ensure dogs are kept away from cat carriers, and reinforce this by asking dog clients to be considerate of cats in the waiting area; • Try to ensure cats are not left to wait for excessive periods of time in the waiting room, but are able to move to the consulting room as quickly as possible; • Direct visual contact with other cats can also be very threatening. This can be overcome in many ways such as erecting small partitions between seats to separate cats in the waiting area, or providing clean blankets or towels to cover the cat’s carrier; • Cats feel insecure if placed at floor level – having shelves, tables or chairs to place cat carriers on so they are raised up is very useful (Fig. 2). These should ideally be about 1.20 m from the ground and have partitions (or use covers) so that cats are not confronted with each other; • Using a plug-in synthetic feline facial pheromone diffuser (Feliway, Ceva Animal Health) may also be of benefit in the environment. Fig. 2 Having raised tables or shelves above floor level for owners to place the cat basket on while in the waiting room is another good way to provide reassurance to cats and help reduce anxiety Approach to the Feline Patient: General and Dermatological Examination 71 VetBooks.ir The Consultation Room Where possible, a clinic should use a dedicated feline consulting room, free from the odor of dogs and other animals. For dermatologic examinations the room should be well lit, but with the ability to darken the room if needed (for example for evaluation with a Wood’s Lamp). There should also be access to an illuminated medical magnifier. Consideration should be given to allowing the cat to wander freely in the consulting room if it chooses, and so it is important there are no cupboards or furniture in the room that the cat could hide under, or small gaps that would make it difficult to retrieve the cat. The consulting room table should also have a clean non-slip surface so that the cat is able to grip well – this can be achieved with a rubber mat or perhaps a clean thick towel or blanket. The use of synthetic feline facial pheromone sprays and diffusers in the consulting room may help to encourage a more relaxed atmosphere, but this is not a substitute for good empathetic handling techniques. The Consultation Process The aim of the consultation process should be to obtain a full history, undertake a full physical examination, and consider what further actions or investigations may be required in conjunction with the owner, while ensuring the cat remains as stress-free as possible. Irrespective of the suspected cause of the skin disease, a full history and full clinical examination should never be overlooked as there may be concurrent disease present and/or a systemic cause of the skin condition. A properly conducted dermatologic consultation, including ancillary tests, usually requires 45–60 minutes. About 20 minutes are dedicated to collecting and recording the signalment and history, examination of the patient requires about 10 minutes and the ancillary tests and discussions with the owner each require about 15 minutes. The times are indicative only and vary depending on the nature of the problem and the communicative ability of the owner. The principles of “cat-friendly” handling should be adhered to at all times – see the AAFP/ISFM Feline-Friendly Handling Guidelines [3] – and the cat should be given time to acclimatize to this unfamiliar environment. History Taking Collecting and reviewing information on the medical and surgical history of the cat is a part of the routine healthcare examination. The history should be collected, as far as possible, in a systematic way – using a clinical history form is a valuable way of obtaining standardized data for all patients (Figs. 3, 4 and 5). A. H. Sparkes and C. Noli VetBooks.ir 72 Fig. 3 Example of a feline clinical history form. Copies of this form are freely available from www.catcare4life.org 73 VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination Fig. 4 Example of a feline nutritional history form. Copies of this form are freely available from www.catcare4life.org A. H. Sparkes and C. Noli VetBooks.ir 74 Fig. 5 Example of a feline physical examination form. Copies of this form are freely available from www.catcare4life.org VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination 75 Clinical history and/or health questionnaires (e.g., including behavior, mobility, routine prophylactic therapy, and general health) can be given to owners to fill out, as far as possible, before bringing their cat to the clinic or while in the waiting room before the consultation. The assistance of a nurse or member of support staff may be valuable, but collecting such information before the consultation itself helps to streamline the process and gather all relevant information. In particular for dermatological consultations it is highly desirable to record all the data collected on a special dermatological clinical record form. This form should be divided into sections for the signalment, history, clinical examination, list of differential diagnoses, ancillary tests, definitive diagnosis, therapy and follow-up (Fig. 6). Many of the issues may be obvious, and may be a part of the existing medical record if the cat is a long-standing patient at the clinic. However, it is important to remember that some owners take their cat to more than one veterinary clinic, so other relevant problems the cat may have suffered should not be overlooked. Even when an accurate history is known, it is still important to consider: • Any current medications (prescribed by the clinic or obtained elsewhere) • Any non-prescription medications the owner may be using (e.g., nutritional supplements, parasiticides, alternative medications, etc.) • Lifestyle (indoors, outdoors, other animals in the house, etc.) In particular, questions regarding the skin disease for which the cat is presented should include: • • • • age of onset/duration of the problem; seasonality; initial site and lesion type and its modification during the course of the disease; severity and localization of pruritus, if present (Tables 1 and 2). Reviewing the history during the clinical examination is an ideal opportunity to open the cat carrier and allow the cat time to come out voluntarily and explore the room. This helps acclimatize the cat to the environment and helps reduce stress during the subsequent examination. History-taking should always include the use of open-ended questions such as: • “How has Fluffy been doing since the last visit?” • “Have you noticed any change in his appetite recently?” • “Has there been any change in Fluffy’s stool consistency?” These are always better than leading questions such as: • “Have you seen any diarrhea?” • “Has he been eating more recently?” VetBooks.ir 76 Fig. 6 Example of a feline dermatological examination history form A. H. Sparkes and C. Noli VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination Fig.6 (continued) 77 VetBooks.ir 78 Table 1 Feline skin diseases and potential severity of pruritus Table 2 Feline skin diseases and most frequent localization of pruritus A. H. Sparkes and C. Noli Potential severity of pruritus Absent Non-inflammatory alopecia Demodicosis (D. cati, uncomplicated) Dermatophytosis (uncomplicated) Moderate Feline atopic syndrome (uncomplicated) Adverse reaction to food (moderate severity) Bacterial infection Malassezia infection Demodicosis by D. gatoi or by D. cati Cheyletiellosis Severe Severe food allergy Severe Malassezia infection Notoedric mange Most frequent localization of pruritus Dorsum Flea bite allergy Cheyletiellosis Psychogenic (licking) Other allergies Head Otodectic mange Adverse reaction to food Notoedric mange Neck Flea bite allergy Adverse reaction to food Idiopathic neck lesion (consider welfare issues) Abdomen (self-induced alopecia in cats from licking) Feline atopic syndrome Flea bite allergy Adverse reaction to food Flea infestation Cheyletiellosis Psychogenic Importantly, a full history should also include a good nutritional assessment (Fig. 4), evaluating the cat’s diet, lifestyle, feeding habits, etc. It is important that this is as comprehensive as possible and covers everything the cat has access to. The cat’s behavior and environment should not be overlooked. This will include whether the cat has free access outdoors, what other animals it regularly has contact with and whether the cat is known to hunt. It is also important to consider the potential interplay between many medical and behavioral issues, including dermatoses (e.g., psychogenic dermatoses). Approach to the Feline Patient: General and Dermatological Examination 79 VetBooks.ir Physical Examination Patience, gentleness, and empathy are vital characteristics with cats in the consultation room. Even with the best environment and approach, some cats will remain very anxious and a full physical examination may not always be possible at the first attempt. Be prepared to take additional time if needed, and in some cases consider scheduling another appointment, or hospitalizing the cat if necessary. As with the history taking, using a standardized form for physical examination and additional forms for special investigations such as dermatological examinations will be highly valuable (Figs. 5 and 6). Using a standardized form will ensure that the physical examination is performed systematically and that nothing is missed. This can be particularly important in cats as the order of events during the examination may have to be flexible and adapted to the needs of the individual cat (see below). Important considerations during the physical examination include: • Don’t ever rush when examining a cat – taking a little extra time to do things slowly and at the cat’s pace will be much more rewarding and less stressful. • Always try to let the cat come out of its carrier by itself. • Be flexible and let the cat choose – allowing the cat some control through exercising choice is a key method to reduce anxiety. The key is to find out and understand what makes the cat more relaxed and adapt the physical examination to suit the individual cat. Some cats may be happier on their owner’s lap, others on the floor. Some may enjoy looking out of a window, while others prefer to stay sitting in their carriers or even hiding under a blanket. Try to be as adaptable as possible, be gentle, and take your time. • Give the cat plenty of fuss and attention if that is what it likes, talk gently and aim to complete the majority of the physical examination without the cat realizing you are doing anything more than just stroking it. • Providing some treats, if the cat will eat them, may also help to distract the cat. • Sitting with the cat on the floor often helps and can make handling much easier. • Some cats prefer to lie down, while others prefer to stand – try to do as much as possible with the cat in its preferred position. • Always use the minimal amount of restraint necessary – any form of overt or heavy restraint will signal danger to the cat and escalate anxiety. • Where needed, split the examination into short sections, and in between allow the cat to rest, change position, or wander round the room – give the cat a short break as soon as it starts to get restless. • As sustained eye contact with a cat can be perceived as threatening by the cat, avoid direct eye contact where possible, and perform as much of the examination as possible with the cat facing away from you (Fig. 7). • Be aware that older cats often suffer from osteoarthritis, which may make handling uncomfortable or painful. • Perform more invasive examinations (such as taking the cat’s temperature, where necessary) to last. VetBooks.ir 80 A. H. Sparkes and C. Noli Fig. 7 The physical examination should be conducted gently and empathetically. Conducting much of the examination from behind the cat avoids direct eye contact which cats often perceive as threatening In particular, for a dermatological examination, the following should be evaluated before any manipulation: • • • • • Nutritional status Coat luster Thickness of the coat Any odors Localization of any obvious lesions When possible the coat and skin should be inspected systematically. The authors normally follow a precise sequence so as not to forget any part of the body. 1. Rear of the animal –– The area at the base of the tail is examined, extending forward along the dorsum to the neck. –– The areas under the tail, anus, and perianal and perivulvar (females) skin are inspected. –– The hind legs are examined, checking for any linear granulomas. –– The hind feet are checked, examining all the interdigital spaces from underneath and on top. The nail beds are examined and all the nails are exposed and checked. 2. In recumbency –– The medial aspect of the hind limbs and the inguinal and abdominal areas are examined. The external genitalia are inspected, including exteriorizing the penis and opening the vulva. –– The sternal area, axillae, and medial aspect of the front limbs are examined. 3. Side of the animal –– The lateral thorax and neck are examined and then the front leg and foot. –– Examination of the appearance and odor of the external ear. –– Repeat the examination from the other side. 4. Finally, the patient is examined from the front –– The head is inspected, including opening the mouth and examination of the conjunctivae. VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination 81 The whole process should be performed gently and quickly, in order not to stress the patient. In exceptional cases, some cats are so fearful that a full examination is not achievable even with the most patient of handling. This is rare, but heavy restraint (scruffing the cat and pinning it to the table) will only make the experience much worse for the cat. In such cases, consider using chemical restraint to facilitate the examination. Cats should be weighed at every clinic visit, and at least once or twice yearly. The percentage weight change should be calculated at each visit and trends noted. Human pediatric or feline-specific accurate electronic scales should be used if possible for optimum accuracy. Skin lesions and their localization and distribution should be recorded for future reference. These include: Macule A non-raised area of a color different to that of the surrounding skin. Hyperpigmented macules on the skin and mucosae of orange cats represent lentigo simplex (Fig. 8). Erythematous macules may be derived from peripheral vasodilation (as it occurs in many inflammatory skin diseases) or from hemorrhage (petecchiae). An extensive area of erythema is called erythroderma. Depigmented macules are typical of vitiligo in Siamese cats. Papule A small, raised, erythematous lesion, it represents accumulation of inflammatory cells within the skin. Papules are typical, e.g., of the initial phases of eosinophilic granulomas. Papules are also a feature of parasitic skin diseases (mosquito-bite hypersensitivity, Fig. 9) and xanthomas. Pustule An accumulation of inflammatory cells (pus) within or just under the epidermis. In cats, pustules are very rare and most frequently seen with pemphigus foliaceus (Fig. 10). Fig. 8 Brown maculae (lentigo simplex) on the oral mucosae of a red cat VetBooks.ir 82 A. H. Sparkes and C. Noli Fig. 9 Small papules and erosions on the pinna of a cat with mosquito bite hypersensitivity Fig. 10 A pustule on the footpad of a cat with pemphigus foliaceus Vesicle An accumulation of clear or hemorrhagic fluid within or just under the epidermis, a rare lesion often caused by autoimmune skin diseases. Cysts Non-neoplastic well-circumscribed accumulations of liquid or keratin. Multiple apocrine cysts, containing clear fluid, are observed in Persian cats (Fig. 11). Approach to the Feline Patient: General and Dermatological Examination 83 VetBooks.ir Fig. 11 Apocrine cysts on the muzzle of a Persian cat Fig. 12 Numerous nodules on the head of a cat with feline progressive histiocytosis Nodule A raised protuberance caused by the infiltration or proliferation of cells and/ or excessive connective stroma. Nodules are seen in bacterial disease (e.g., abscess), fungal infection (e.g., deep mycosis or dermatophyte mycetoma), sterile reactions (injection site granulomas, feline progressive histiocytosis, Fig. 12), or neoplasia. Plaque A firm, raised area with a flattened surface, e.g., eosinophilic plaque (Fig. 13). Wheal Raised well-circumscribed lesion consisting of edema of the superficial dermis. Wheals have an acute onset (a few hours) and tend to resolve quickly (over VetBooks.ir 84 A. H. Sparkes and C. Noli Fig. 13 Typical aspect of a eosinophylic plaque in an allergic cat Fig. 14 Angioedema of the head of a cat a few hours or 1 day). Wheals are a manifestation of a type 1 hypersensitivity reaction (immediate or anaphylactic) and are seen in reaction to intradermal allergen tests. Angioedema is edema extending to the deeper tissue and involving a larger area of the body (esp. the head, Fig. 14). Comedones Commonly referred to as “blackheads”, they represent an accumulation of keratin in the infundibulum of the hair follicle. Comedones in cats are seen on the chin in feline acne (Fig. 15). Crust The accumulation of dried exudate (Fig. 16) or blood. The color depends on the material from which they were formed (blood = brown, pus = yellow). The eschar (Fig. 17) is a particular type of crust that contains dermal collagen fibers and is thus strongly anchored to the body (i.e., it cannot be easily pulled). Eschars are typically seen in cats in case of idiopathic ulcerative neck lesion and feline perforating dermatitis. VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination Fig. 15 Comedones and furuncolosis on the chin of a cat affected with acne Fig. 16 Several yellow crusts (dry pus) on the pinna of a cat affected with pemphigus foliaceus Fig. 17 An eschar on the neck of a cat affected with feline idiopathic ulcerative dermatitis 85 VetBooks.ir 86 A. H. Sparkes and C. Noli Fig. 18 Dry large flaques of exfoliation in a cat affected with paraneoplastic thymoma- associated exfoliative dermatitis Fig. 19 Self-inflicted excoriations and ulcerations in a cat with adverse food reactions Scale Dry accumulations of layers of the stratum corneum commonly called dandruff (Fig. 18). The presence of scales in cats is usually associated with dermatophytosis, sebaceous adenitis, or paraneoplastic diseases (feline exfoliative dermatitis due to thymoma). Excoriation A self-induced lesion including ulceration and crusts, resulting from scratching and/or biting (Fig. 19). Erosion A loss of epidermis down to the level of the basement membrane but leaving the dermis intact. Erosions are seen in some autoimmune diseases (e.g., pemphigus complex and diseases inducing dermo-epidermal separation) and in early cases of eosinophilic plaque (because of the abrasive action of the feline tongue). Ulcer Tissue loss involving the epidermis and underlying tissues (dermis, less frequently subcutis). Examples of ulcers in cats are deep bacterial (e.g., atypical myco- Approach to the Feline Patient: General and Dermatological Examination 87 VetBooks.ir Fig. 20 Lesion of lip (indolent) ulcer Fig. 21 Self-inflicted alopecia on the abdomen due to licking bacteria) or fungal (e.g., sporotrichosis) infections, for squamous cell carcinoma, idiopathic neck ulcer and lip (indolent) ulcer (Fig. 20). Draining tract An opening in the tissue releasing exudate produced by a deeper inflammatory process (dermis or subcutis). Fistulization of abscesses or other inflammatory foci (sterile panniculitis, foreign body granuloma, etc.) permits the drainage of pus and the eventual expulsion of etiological agents, foreign bodies, or necrotic material. Alopecia Can be used to describe both the complete loss of hair over one or more areas of the body and hypotrichosis, meaning thinning of the hair coat. It is important to differentiate alopecia caused by the loss of the hair together with the root from the loss of part of the hair shaft only. In cases of the loss of the hair root, for example, in endocrine or paraneoplastic alopecia, the hair at the periphery of the lesion can be easily epilated with traction. In the case of broken hair (e.g., self- induced alopecia, Fig. 21), the small remaining ends of the hair can be felt or seen VetBooks.ir 88 A. H. Sparkes and C. Noli with a magnifying lens as they leave the follicular ostia. The hair surrounding the areas of alopecia resists epilation. Diagnostic Investigations There are a number of diagnostic tests that, although mostly very straightforward, are extremely valuable in the diagnosis of various dermatoses. Again, it is important to consider appropriate chemical (sedation) for the cat in order to facilitate these tests wherever necessary. It is far less stressful to use appropriate chemical restraint than to struggle with heavy physical restraint of an anxious or fearful cat. Trichogram A trichogram involves microscopic examination of hairs (tip, shaft, and root) – ideally around 20–30 hairs are plucked and then examined. The preferred instrument to remove the hair is a pair of mosquito hemostats (preferably Klemmer) covered by small rubber or plastic tubing (to obtain even pressure and avoid causing artifacts by damaging the hair). In this way, samples from all stages in the growth cycle will be obtained rather than only resting-phase hairs. The hairs should be plucked in the direction of the hair growth to avoid fracturing them at the base. The hairs can be secured on a microscope slide either by placing them in mineral oil with a coverslip placed on top or using adhesive acetate tape. Examination is performed under 40× and 100× magnification. The hair tips can be examined to determine whether there is pruritus (traumatic epilation) or spontaneous epilation. With traumatic hair loss the tips of the hairs will be broken and the usual slender tapering tips will be lost. The hair roots can be examined to determine if the hairs are in anagen or telogen and see if there is normal hair cycling. Most should be in telogen (rough, spear-shaped bulb), with fewer in anagen (expanded bulb, may appear fringed, often pigmented, may appear club-shaped). In shorthair cats around 90% of hairs will be in telogen. Hair shafts should also be examined for abnormalities including the presence of ectoparasites (Demodex cati), ectoparasite eggs (Felicola subrostratus, Chyeletiella spp.), and/or dermatophytes. Large adhesions of keratin on the hair shafts, called follicular casts, are seen in sebaceous adenitis. Skin Scraping A small window of skin is clipped if necessary. A small amount of mineral oil can be put on the skin surface to facilitate the skin scraping and a blunted scalpel blade or a Volkmann spoon (diameter 5–6 mm) is held perpendicular to the skin surface, which is scraped in the direction of the hair growth using moderate pressure. For superficial parasites such as Notoedres cati and Demodex gatoi, scraping should not be so deep to cause capillary oozing of blood. The collected material can be smeared on a slide for examination. Deep skin scraping involves repeated scraping at the same site until there is capillary oozing of blood. Pinching the skin prior to scraping to “squeeze” contents out from the follicles may also facilitate collection of follicular material and follicular VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination 89 Demodex mites. In untreated patients with demodicosis, the number of mites detected is usually very high and hence it is rarely necessary to collect more than 2 or 3 samples and trichoscopy may be preferable over skin scrapings. When monitoring therapeutic success the mite numbers are low and numerous deep skin scrapings are necessary. Examination of skin scrapes is performed under 40× to 400×, but initial examination should always be done at 40×. If there is heavy keratinous debris, taking “dry” skin scrapes and suspending the collected material in 10–20% potassium hydroxide which is then left for 20–30 minutes before examination under a coverslip may enhance visualization through “clearing” of the keratinous debris. ape Strip Test (“Scotch Tape” or “Acetate Tape” Test) T This test allows collection of superficial skin parasites, hairs, and yeasts. A 5–8 cm strip of clear sticky tape is repeatedly applied to the lesion or area of skin of interest. The skin can be clipped prior to performing the test if necessary. The tape is then applied (stuck) to a microscope slide. The free ends can be wrapped around the slide to help anchor it. The preparation can be stained if necessary (e.g., looking for Malassezia) by applying a drop of suitable stain (e.g., the “blue” Diff-Quik stain) to the slide before applying the sticky tape. The slide is examined under 40× to 400× magnification. Coat Brushings Coat brushings are particularly helpful to look for fleas, but may also provide evidence of other superficial parasites. The cat is placed on a large sheet of white paper and is brushed vigorously both with and against the growth of the hair. Scale and debris are collected, are examined macroscopically, and can be placed on a slide and examined in mineral oil or a stain such as lactophenol cotton blue. Combing with a flea comb may also be a useful part of the procedure. ood’s Lamp Illumination W Wood’s lamp illumination is used to examine the hair coat (or collected hairs) under ultraviolet light to look for spontaneous fluorescence that is often associated with Microsporum canis infection. For optimal results, it is important to use the Wood’s lamp in a dark room, and to allow 30–60 minutes for the eyes to adapt to the low light conditions. More information regarding this technique is presented in the chapter dealing with dermatophytosis (Chapter, Dermatophytosis). Cytology Several techniques have been developed to obtain material for a cytological examination. Fine Needle Aspiration This technique is used for raised lesions, nodules, or accessible lymph nodes. A 21G (gray) needle is inserted into the center of the nodule and connected to a 5 or 10 ml syringe. While the needle is inside the mass several 1–2 ml aspirates are made, changing the needle position (angulation) without withdrawing the needle from the lesion. The suction is completely released before VetBooks.ir 90 A. H. Sparkes and C. Noli withdrawing the needle. If this has been done correctly, the plunger should return to 0 ml and the cells will be located in the needle lumen. If the plunger fails to return to zero, air has entered the syringe and the procedure should be repeated because the cells are in the cone of the syringe and difficult to remove. The needle is then removed from the cone and the syringe filled with air, reconnected to the needle and the cells are “sprayed” onto a microscope slide. If the sample is liquid, a smear is made, similar to that used for blood. If the material is solid, the material is spread by placing a second slight over the sample, applying little or no pressure. Fine Needle Insertion A 24G needle is inserted into the mass and its angle changed, without connection to a syringe. The needle is then removed from the lesion, connected to a syringe filled with air and the samples are sprayed onto a slide and spread as described above. This technique is particularly indicated for lymph nodes, for very small lesions or when excessive blood is obtained with aspiration. Impression Smear Impression smears are used for exudative lesions, superficial oily accumulations, pustules, crusts, or biopsy specimens cut in half. The slide is placed several times lightly onto the lesion or oily area. To sample a pustule or a crust, the lesion is opened with a 24G needle and a slide is applied to the drop of pus that comes out. Impression smears have the advantage of not deforming the cells but often result in a sample that is too thick. In such cases, search around the margins of the slide for a monolayer of cells. Superficial Skin Scrapings As previously described, Malassezia can be demonstrated with a very superficial skin scraping of seborrheic skin by using a number 10 or 20 scalpel blade. The material is spread onto a microscope slide using the blade, fixed using a flame and stained with a standard stain. Sampling with a Cotton Bud This technique is useful for collecting samples from draining tracts, interdigital spaces, claw folds, and external ear canals. The sample is applied to a slide by gently rolling the cotton bud. Skin Biopsy Skin biopsies are sometimes needed for investigation and diagnosis of dermatoses. If the condition of the patient permits, it is better to perform the biopsy after 1–2 weeks of antibiotic therapy. This removes any secondary infection that can complicate the interpretation of the biopsy. Preferred antibiotics include cephalexin (20–30 mg/kg orally twice daily), cephadroxil (20–30 mg orally twice daily), or amoxicillin-clavulanate (20–25 mg orally twice daily). To avoid secondary infection and scarring, the antibiotic can be continued for 1 week after the biopsy. If the patient has been receiving glucocorticoid therapy and the condition of the patient permits, then the biopsy should be delayed until 15–20 days after treatment discontinuation or longer if long-acting depo-injections have been used. VetBooks.ir Approach to the Feline Patient: General and Dermatological Examination 91 Local anesthesia would be preferable, given that the procedure is minor and rapid and requires only one or two sutures, however in cats this is possible only if they are extremely quiet and when biopsies are taken from the trunk. If using local anesthesia, one should remember that no more than 1 ml of 2% lidocaine should be injected in cats, due to risk of cardiac toxicity. If multiple biopsies are necessary, lidocaine can be diluted 1:1 with saline, so that 2 ml of 1% lidocaine are obtained and can be used for up to 4 biopsies. In the majority of cases, however, general anesthesia is used. In general, collecting several biopsies from representative lesions will facilitate the diagnosis. Wherever possible, early lesions, such as papules and pustules should be biopsied, and later evolution of these, such as ulcers and crusts should be avoided, however, if there is a range of lesions, biopysing all is prudent. Prior to biopsy, lesions may be gently clipped, but it is preferable not to clean the skin as this may remove valuable diagnostic material. Disposable punch biopsies are usually the preferred method of biopsy collection. Biopsies from the edge of lesions, including adjacent apparently normal-looking skin, should be obtained with the elliptical excision biopsy technique. The sample should be put in 10% fresh formalin and accompanied by a full clinical history. The pathologist should be informed of the signalment (age and breed), clinical signs, description and site of the lesions, and duration and evolution of the disease. Any treatment/medication, its duration and period of suspension should be included. Biopsies from different sites should be submitted in separate, numbered containers with a description in the history indicating the site and type of lesion for each biopsy. References 1. Pankratz KE, Ferris KK, Griffith EH, et al. Use of single-dose oral gabapentin to attenuate fear responses in cage-trap confined community cats: a double- blind, placebo-controlled field trial. J Feline Med Surg. 2018;20:535–43. 2. Van Haaften KA, Eichstadt Forsythe LR, Stelow EA, Bain MJ. Effects of a single pre- appointment dose of gabapentin on signs of stress in cats during transportation and veterinary examination. J Am Vet Med Assoc. 2017;251:1175–81. 3. Rodin I, Sundhal E, Carney H, et al. AAFP and ISFM Feline-Friendly Handling Guidelines. J Feline Med Surg. 2011;13:364–75. VetBooks.ir Part II Problem Oriented Approach to…: VetBooks.ir Alopecia Silvia Colombo Abstract Alopecia, either spontaneous or self-induced, is a common presenting sign in cats. Definitions of alopecia and hypotrichosis and the clinical features of alopecia are given at the beginning of this chapter, followed by pathogenesis of the different types of alopecia. Clinical presentations of alopecia and its preferential localization in selected feline diseases are described, together with useful diagnostic hints coming from signalment and history. The diagnostic approach to alopecia implies the correct differentiation of the pathogenetic mechanisms underlying the clinical signs, which can be obtained by collecting history, examining the cat, and performing a microscopic examination of the hair. This is, in cats, a very important diagnostic test, which should always be performed at the beginning of the consultation, in order to differentiate spontaneous from self- induced alopecia. Dermatophytosis is very common in cats, and diagnostic tests to diagnose or rule out this disease should be carried out in all cases presenting with alopecia. Definitions Alopecia simply means hair loss. The word alopecia is derived from the ancient Greek word ἀλώπηξ (alṓpēx), which means fox. The term “alopecia” was used at that time to describe fox mange. Hypotrichosis means that there is less than normal amount of hair (from the ancient Greek words υπο, below, and θριξ, hair), and this term is sometimes used as a synonym of partial alopecia. Although the exact meaning of these two terms is very similar, if not identical, the term hypotrichosis is preferred when there is a S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_4 95 VetBooks.ir 96 S. Colombo Fig. 1 Congenital hypotrichosis in a domestic short-haired kitten congenital deficiency of hair in both human and veterinary dermatology publications (Fig. 1) [1]. Strictly speaking, hypotrichosis should be used as a synonym of congenital alopecia. Alopecia can be classified depending on severity (partial or complete), distribution (focal, multifocal, generalized, symmetrical), localization, and pathogenesis. Partial alopecia means that there is less than normal amount of hair, while complete alopecia describes absence of hair. Focal alopecia, occasionally also called localized alopecia, refers to a single patch of alopecia anywhere on the body (Fig. 2). If more patches are present, alopecia is defined as multifocal. Focal or multifocal alopecia in cats is a clinical presentation commonly observed in cases of dermatophytosis (Fig. 3). When a whole region of the body is involved, alopecia is described as diffuse or generalized. Diffuse alopecia may be symmetrical, when both sides of the body are equally affected. Generalized alopecia is normal in hypotrichotic breeds, such as the Sphynx cat [2]. Pathogenesis In cats, the most useful classification of alopecia from a diagnostic point of view is the one based on pathogenesis. Alopecia can be spontaneous, when the hair falls off, or self-induced, when the cat actively removes the hair by continuous licking. Spontaneous alopecia occurs as a consequence of two main pathogenetic mechanisms. When inflammation or infection targets the hair follicle and/or the hair shaft, the latter undergoes damage and falls off (Fig. 4). Hair may also be absent because the hair follicle is dysplastic or atrophic, thus not able to produce a normal hair shaft (Table 1). VetBooks.ir Alopecia 97 Fig. 2 Focal alopecia on the front limb in a kitten affected by dermatophytosis Fig. 3 Multifocal alopecia in a kitten affected by dermatophytosis Fig. 4 Spontaneous alopecia following an adverse reaction to flea collar in an adult cat Self-induced alopecia is caused by the cat itself by excessive licking and, less commonly, by chewing, plucking hair, or scratching (Fig. 5). Licking in the feline species is a major component of grooming, a normal, genetically programmed feline behavior. Cats groom to remove dead hair, ectoparasites and dirt and to control body temperature. One study suggested that a healthy cat grooms for approximately 1 hour per day [3]. An increased frequency and/or intensity of this behavior is called 98 VetBooks.ir Table 1 Selected causes of spontaneous alopecia S. Colombo Inflammation/infection of the hair follicle Dysplasia/atrophy of the hair follicle Fig. 5 Self-induced alopecia in an allergic cat Pyoderma Dermatophytosis Demodicosis (Demodex cati) Pemphigus foliaceus Pseudopelade Lymphocytic mural folliculitis Sebaceous adenitis Topical/injectable glucocorticoid administration Topical/systemic adverse drug reaction Telogen effluvium Spontaneous/iatrogenic hyperadrenocorticism Paraneoplastic alopecia Post-traumatic alopecia Alopecic breeds/congenital hypotrichoses Pili torti Cicatricial alopecia (scar) Alopecia Pruritus VetBooks.ir Table 2 Selected causes of self-induced alopecia 99 Pain/neurologic Behavioral Pyoderma Dermatophytosis Malassezia overgrowth Flea infestation Cheyletiellosis Otodectic mange (erratic) Demodicosis (Demodex gatoi) Lynxacarus infestation Flea-bite hypersensitivity Adverse reaction to food Feline atopic syndrome Allergic contact dermatitis Feline lymphocytosis Feline hyperesthesia syndrome Irritant contact dermatitis Feline idiopathic cystitis Trauma Psychogenic alopecia overgrooming and may be the expression of pruritus, pain or behavioral problems (Table 2). Being the increased expression of a physiological behavior, overgrooming is often not recognized by the owner or not interpreted as a sign of pruritus or pain. Moreover, cats tend to express their discomfort by hiding away from the owners, who may not be aware of their pet’s overgrooming. Finally, one must remember that some diseases may cause both spontaneous alopecia due to damage to the hair follicle and self-induced alopecia due to pruritus. For example, some cases of dermatophytosis or demodicosis may be associated with pruritus. Diagnostic Approach Signalment and History Infectious and ectoparasitic diseases such as dermatophytosis, demodicosis, flea infestation, or cheyletiellosis are commonly observed in kittens or in environmental conditions of crowding, such as breeding colonies or pet shops. Paraneoplastic syndromes and neoplasia are typically seen in older cats. Breed may be a relevant information in the diagnostic approach: Persian cats are predisposed to dermatophytosis (Fig. 6); congenital hypotrichosis has been recently reported in Birman cats [1]. A good knowledge of feline phenotypes is important, especially for breeds such as the Devon rex cat, which may have an extremely variable amount of hair on the trunk and is physiologically alopecic on the lateral and ventral neck. History is also very relevant for the diagnosis. A scar may be easily diagnosed based on history, while previous trauma from a car accident or a fall may point towards a post-traumatic alopecia [4]. A detailed pharmacological history is VetBooks.ir 100 S. Colombo Fig. 6 Alopecia and scaling on the tail of a Persian cat with dermatophytosis Fig. 7 Spontaneous alopecia in an old cat affected by hyperadrenocorticism and demodicosis important when an adverse drug reaction is suspected. Sudden onset of alopecia in a queen that recently gave birth may suggest telogen effluvium. Seasonality of self-induced alopecia may orientate towards feline atopic dermatitis. Concurrent systemic clinical signs such as polyuria and polydipsia in an old, diabetic cat developing spontaneous alopecia should prompt testing for hyperadrenocorticism (Fig. 7), while self-induced alopecia of the abdomen and groin may be caused by feline idiopathic cystitis [5]. Clinical Presentation Spontaneous alopecia may be partial or complete and, in general, hair can be easily epilated from the whole alopecic area, from the center of the lesion or from its periphery. The skin looks glabrous and smooth, and few short fragments of hair can be seen emerging from follicular ostia in selected diseases such as dermatophytosis. VetBooks.ir Alopecia 101 Fig. 8 Close-up image of the abdominal skin of a cat with self-induced alopecia Self-induced alopecia is characterized by the presence of very short fragments of hair which can be observed by looking closely at the skin or with the help of a magnifying lens (Fig. 8). Hair cannot be easily epilated. Self-induced alopecia is often complete and may be symmetrical. The alopecic area usually has very well-defined margins, with abrupt change to normal hair. Both spontaneous and self-induced alopecia in cats may be focal, multifocal or generalized, and may be associated with other skin lesions. The presence/absence and type of lesion accompanying alopecia is extremely useful to orient the diagnostic process (Table 3). Focal alopecia and thickening of the affected skin, together with history of previous trauma, may allow the clinician to identify a scar. The skin may also be hypo- or hyperpigmented. Mild erythema and exfoliation associated with focal or multifocal alopecia in cats may suggest dermatophytosis. Pruritus may vary from absent to moderate and for this reason dermatophytosis should also be considered in the list of differential diagnoses of self-induced alopecia. A focal area of non-inflammatory alopecia with very thin skin, visible blood vessels and bruising suggests a reaction to one or repeated glucocorticoid injections in that site (Fig. 9). Generalized, predominantly ventral alopecia with shiny skin in an old cat is suggestive of paraneoplastic alopecia (Fig. 10) [6]. Focal or multifocal alopecia and erythema, mild scaling and occasionally comedones, associated with mild or no pruritus may be indicative of demodicosis due to Demodex cati, a follicular mite that usually causes disease in immunocompromised animals. Severe pruritus and self-induced alopecia with erythema and scaling raises the suspicion of demodicosis due to Demodex gatoi, a contagious, short-bodied mite living in the stratum corneum. Demodicosis is uncommon in the cat [7]. Severe scaling and self-induced alopecia, often with a dorsal distribution, may indicate cheyletiellosis. Self-induced alopecia, particularly if miliary dermatitis and/ or eosinophilic plaques are concurrently observed, may be very suggestive of an allergic disease. 102 S. Colombo VetBooks.ir Table 3 Examples of lesions observed concurrently to alopecia in feline skin diseases Spontaneous alopecia Self-induced alopecia Lesions Erythema, scaling, follicular casts Disease Dermatophytosis Erythema, scaling, comedones, follicular casts Papules, crusting, scaling Pustules, yellow crusting Onychomadesis, onychorrhexis Scaling, hyperpigmentation Scaling, crusting, follicular casts Focal thinning, visible blood vessels, bruising None Thin skin, bruising, tears, scaling, comedones Shiny skin Erythema, shiny skin, erosions/ulcers Absence of whiskers, claws, tongue papillae Thickening, hypo-/hyperpigmentation Scaling Demodicosis Ceruminous otitis externa Miliary dermatitis, eosinophilic plaque Papules, crusting, scaling Erythema, scaling, ceruminous otitis externa, paronychia, chin acne Erythema, erosions/ulcers, plaques Skin rolling Erosions/ulcers None None Otodectic mange (erratic) Allergic diseases Superficial pyoderma Malassezia overgrowth Fig. 9 Spontaneous, focal alopecia in a cat treated with repeated injections of a glucocorticoid Superficial pyoderma Pemphigus foliaceus Pseudopelade Lymphocytic mural folliculitis Sebaceous adenitis Topical/systemic glucocorticoid administration Telogen effluvium Spontaneous/iatrogenic hyperadrenocorticism Paraneoplastic alopecia Post-traumatic alopecia Congenital hypotrichoses Scar Cheyletiellosis Feline lymphocytosis Feline hyperesthesia syndrome Trauma Feline idiopathic cystitis Psychogenic alopecia VetBooks.ir Alopecia 103 Fig. 10 Diffuse alopecia and shiny skin on the abdomen of a cat with paraneoplastic alopecia Together with the correct distinction between spontaneous and self-induced alopecia and identification of concurrent lesions, preferential localization of the clinical signs may help in listing the differential diagnoses (Table 4). Diagnostic Algorithm This section is illustrated in Fig. 11. Red squares with numbers represent the steps of the diagnostic process, as explained below. 1 Perform microscopic hair examination Microscopic examination of hair shafts is the first test to perform in any case of alopecia in cats since it may yield useful information, beyond the distinction between spontaneous and self-induced alopecia. First, the hair tips must be evaluated: broken tips indicate self-induced alopecia, while intact tips may indicate spontaneous hair loss, with the exception of dermatophytosis. Second, the hair shaft in its entire length should be carefully observed. Congenital abnormalities, such as pili torti, present with flattened hair shafts that twist on their own axis by 180 degrees at irregular intervals 104 S. Colombo VetBooks.ir Table 4 Common locations of alopecia in selected feline skin diseases Spontaneous alopecia Distribution Head, pinnae, paws, tail, generalized Head, neck, ear canal, generalized Head, pinnae, claw folds, abdomen Head, abdomen, legs, paws Head, pinnae neck, generalized Site of application/injection Trunk Abdomen, ventral trunk, medial legs Rump Generalized Site of previous trauma Self-induced alopecia Rump Dorsum Neck, rump, tail, ear canal Thorax, abdomen Rump Abdomen, medial thighs, head, neck Chin, claw folds, face, ear canal, generalized Thorax, legs, pinnae, neck Dorsum Abdomen, groin Site of previous trauma 2 Disease Dermatophytosis Demodicosis Pemphigus foliaceus Pseudopelade Sebaceous adenitis Topical/systemic glucocorticoid administration Spontaneous/iatrogenic hyperadrenocorticism Paraneoplastic alopecia Post-traumatic alopecia Alopecic breeds/congenital hypotrichoses Cicatricial alopecia (scar) Flea infestation Cheyletiellosis Otodectic mange (erratic) Demodicosis Flea-bite hypersensitivity Other allergic diseases Malassezia overgrowth Feline lymphocytosis Feline hyperesthesia syndrome Feline idiopathic cystitis Post-traumatic alopecia (Fig. 12) [8]. Moving towards the root, spores of dermatophytes arranged around the hair shaft or Demodex mites free or embedded in keratin casts may be identified. However, a negative result of hair examination does not rule out dermatophytosis and demodicosis. Rule out non-dermatological causes of self-induced alopecia When the microscopic examination of hair shafts indicates self-induced alopecia, non-dermatological causes must be carefully considered and history should specifically investigate for concurrent non-dermatological signs. If the alopecia occurs on the abdomen and groin only, urinalysis and bacterial culture and sensitivity testing should be performed to investigate feline idiopathic cystitis, urolithiasis and/or lower urinary tract infections. Ultrasound examination may help investigate other causes of abdominal pain. If the alopecia is focal and located, for example, on a single limb or on the dorsal spine, an x-ray examination may identify a previous trauma which may explain the cat’s continuous licking at that site. When abnormal behavior such as rippling or rolling the skin along the lumbar spine is reported by the owner to occur frequently, a neurological examination should be recommended [9]. Alopecia 105 Alopecia VetBooks.ir 1 Self-induced Pili torti Demodicosis Dermatophytosis Demodicosis Skin scraping Dermatophytosis Wood’s lamp examination 5 Cytology Trauma 3 Telogen effluvium Complete blood count Biochemistry Urinalysis 6 Ultrasound Endocrinology testing TC/MRI Fungal culture Feline idiopathic cystitis Scar Topical/systemic glucocorticoid administration 4 X-ray Urinalysis Bacterial culture and sensitivity testing Ultrasound Neurologic examination (if appropriate) Feline hyperesthesia syndrome Spontaneous History Superficial pyoderma 2 Hair examination Go to chapter 9 Pruritus Spontaneous/iatrogenic hyperadrenocorticism 7 Pemphigus foliaceus Histopathology Paraneoplastic alopecia 8 X-ray Post-traumatic alopecia Pseudopelade Lymphocytic mural folliculitis Sebaceous adenitis Congenital hypotrichoses Topical/systemic adverse drug reaction Fig. 11 Diagnostic algorithm of alopecia Fig. 12 Microscopic examination of the hair shaft of a cat with pili torti (10X) 3 Finally, if all these potential causes of alopecia do not comply with the history and clinical presentation or have been ruled out, self-induced alopecia should be further investigated following the diagnostic approach to pruritus (Chapter, Pruritus). Consider the patient’s history Spontaneous focal alopecia associated with variations of skin thickness and history of a wound in that site points towards a diagnosis of scar. If a topical glucocorticoid has been applied or a glucocorticoid injection has been given VetBooks.ir 106 4 5 6 7 8 S. Colombo where alopecia developed and the skin appears thin, with bruising and visible vessels, the diagnosis is straightforward and may be supported by the observation of mostly telogen hair roots on microscopic examination. Sudden onset of diffuse alopecia in a queen who recently gave birth, for example, may suggest telogen effluvium. In this case, the remaining hair is easily epilated and microscopic examination of hair shows telogen roots only. Perform skin scrapings Skin scrapings are diagnostic for demodicosis and, together with microscopic examination of hair, may be strongly suggestive of dermatophytosis. In fact, the correct identification of dermatophyte spores surrounding hair shafts may be easier on skin scrapings than microscopic examination of hair shafts, because scraping the surface of the alopecic area is likely to collect more broken, infected hair [10]. Perform Wood’s lamp examination and fungal culture These two diagnostic tests, taken together, are diagnostic for dermatophytosis or, if negative results are obtained, are helpful to rule it out. Since dermatophytosis is the most common cause of alopecia in cats, a fungal culture is appropriate in all cases presenting with alopecia. Consider non-dermatological clinical signs In an old cat presenting with alopecia and systemic signs such as polyuria/ polydipsia, polyphagia, vomiting or weight loss, one must consider the possibility of alopecia being caused by a systemic disease. If the alopecic skin appears thin, with bruising and/or tears developing after minimal traction, the cat should be investigated for hyperadrenocorticism. History may suggest iatrogenic hyperadrenocorticism, if glucocorticoids have been administered for a long time, or spontaneous hyperadrenocorticism if there is no history of glucocorticoids administration or the cat is diabetic. Ventrally distributed alopecia with shiny skin in a cat presenting with concurrent weight loss, depression, vomiting, and/or diarrhea may point towards a diagnosis of paraneoplastic alopecia and should prompt to perform an abdominal ultrasound examination. Perform cytology Cytology should be performed if other lesions, such as pustules, crusts or erosions/ulcers are present together with alopecia. The observation of large numbers of degenerate neutrophils with intracellular and extracellular bacteria indicates superficial pyoderma. If the neutrophils appear “healthy” and many acantholytic keratinocytes are seen, the results of cytological examination are suggestive of pemphigus foliaceus. If large numbers of eosinophils are seen, it is more likely that the cat is pruritic and alopecia should be further investigated following the diagnostic approach to pruritus (Chapter, Pruritus). Take biopsies for histopathological examination Histopathological examination may be useful to confirm paraneoplastic alopecia and should always be performed if pemphigus foliaceus is suspected. Some diseases presenting with alopecia can only be diagnosed with histopathology; examples are pseudopelade, sebaceous adenitis, congenital hypotrichosis, and VetBooks.ir Alopecia 107 adverse drug reactions. If the histopathological examination is suggestive of post-traumatic alopecia, radiological examination of the pelvis should be carried out to confirm the diagnosis. References 1. Abitbol M, Bossé P, Thomas A, Tiret L. A deletion in FOXN1 is associated with a syndrome characterized by congenital hypotrichosis and short life expectancy in Birman cats. PLoS One. 2015;10:1–12. 2. Genovese DW, Johnson TL, Lamb KE, Gram WD. Histological and dermatoscopic description of sphynx cat skin. Vet Dermatol. 2014;25:523–e90. 3. Eckstein RA, Hart BL. The organization and control of grooming in cats. Appl Anim Behav Sci. 2000;68:131–40. 4. Declerq J. Alopecia and dermatopathy of the lower back following pelvic fractures in three cats. Vet Dermatol. 2004;15:42–6. 5. Amat M, Camps T, Manteca X. Stress in owned cats: behavioural changes and welfare implications. J Feline Med Surg. 2016;18:1–10. 6. Turek MM. Cutaneous paraneoplastic syndromes in dogs and cats: a review of the literature. Vet Dermatol. 2003;14:279–96. 7. Beale K. Feline Demodicosis. A consideration in the itchy or overgrooming cat. J Feline Med Surg. 2012;14:209–13. 8. Maina E, Colombo S, Abramo F, Pasquinelli G. A case of pili torti in a young adult domestic short-haired cat. Vet Dermatol. 2013;24:289–e68. 9. Ciribassi J. Feline hyperesthesia syndrome. Compend Contin Educ Vet. 2009;31:116–22. 10. Colombo S, Cornegliani L, Beccati M, Albanese F. Comparison of two sampling methods for microscopic examination of hair shafts in feline and canine dermatophytosis. Vet Dermatol. 2008;19(Suppl. 1):36. General References For definitions: Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 10 May 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Mecklenburg L. An overview on congenital alopecia in domestic animals. Vet Dermatol. 2006;17:393–410. Miller WH, Griffin CE, Campbell KL. Muller & Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Papules, Pustules, Furuncles and Crusts Silvia Colombo Abstract Papules, pustules, furuncles, abscesses and crusts are common lesions in cats. With the exception of abscesses, they are often observed in combinations, representing different stages of the same disease evolving into one another. In general, these lesions are the expression of inflammatory diseases, with infectious, parasitic, allergic or autoimmune pathogenesis. Clinical presentations of papules, pustules, furuncles, abscesses and crusts and their preferential localization in selected feline diseases are described, together with useful diagnostic hints coming from signalment and history. A feline-specific clinical presentation called miliary dermatitis is characterized by multiple, small crusted papules and pruritus. The diagnostic approach to papules, pustules, furuncles, abscesses and crusts requires performing the diagnostic tests in a systematic way. Dermatophytosis is very common in cats, and diagnostic tests to diagnose or rule out this disease should be carried out in all cases presenting with papules, pustules, crusts or as miliary dermatitis. Definitions A papule is a solid, erythematous, elevated skin lesion of less than 1 cm diameter [1]. Many papules close to each other may coalesce to form a plaque (Chapter, Plaques, Nodules and Eosinophilic Granuloma Complex Lesions). A pustule is an elevated, circumscribed, hollow lesion containing pus and covered by epidermis. It may be centered around a hair follicle or may be interfollicular S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_5 109 VetBooks.ir 110 S. Colombo in location. Pustules usually contain neutrophils, with or without bacteria, or less commonly eosinophils. They are fragile and often transient lesions, uncommonly observed in cats. A furuncle is similar to a pustule, but it is larger in size and deeper in location, because it results from the complete destruction of the hair follicle. The wall of a furuncle is thicker than the roof of a pustule, and its content comprises pus, blood (in this case, it is also called hemorrhagic bulla) or a mixture. It is usually a very inflamed and painful lesion, centered around a hair follicle. The furuncle may open and drain pus, blood or a hemopurulent exudate. An abscess is a circumscribed, fluctuant, dermal or subcutaneous collection of pus. It may open and drain on the skin surface, forming a draining tract. A crust is an accumulation of dried exudate. The crust is yellowish when the dried material is pus, or brownish if dried blood is its main component (hemorrhagic crust). It may also contain microorganisms and epidermal cells, such as acantholytic keratinocytes or corneocytes and, if the crust encloses a tuft of hair, its removal results in focal alopecia. Pathogenesis Papules, pustules and crusts represent collections of inflammatory cells in the epidermis (pustule), dermis (papule) or on the skin surface (crust) as dead remnants of these cells. The inflammatory cells are attracted towards the superficial layers of the skin by infectious agents, parasites or allergens, or may be the expression of an autoimmune disease such as pemphigus foliaceus (Fig. 1). The furuncle is a deeper lesion which results from the complete destruction of the hair follicle. The hair follicle is destroyed by severe inflammation, which is, in the feline species, most commonly induced by a bacterial infection as in complicated Fig. 1 Severe crusting due to drying of purulent exudate on the pinna of a cat with pemphigus foliaceus VetBooks.ir Papules, Pustules, Furuncles and Crusts 111 Fig. 2 Furuncles on the chin of a cat affected by complicated chin acne chin acne (Fig. 2) [2]. The hair shaft may be free in the dermis together with bacteria and other debris, and attracts more inflammatory cells behaving as a foreign body. The abscess usually occurs following bite or claw wounds, with implantation of bacteria in the deep dermis and subcutis. The presence of bacteria attracts large numbers of neutrophils and other inflammatory cells at the infection site, until a large collection of pus is formed (Fig. 3). Papules, pustules, furuncles and crusts may represent different stages of the same disease and can evolve into one another. A papule may develop into a pustule, which ruptures and becomes a small crust. Very uncommonly in the cat, a circular rim of scales may form when the crust comes off: this lesion is called epidermal collarette. A pustule may become a furuncle if the infection deepens and extends to involve and destroy the whole hair follicle. If the furuncle opens and drains exudate, a crust may form. When the crust comes off, an area of focal alopecia is the final result. Crusts may also cover other lesions, such as erosions and ulcers (Chapter, Excoriations, Erosions and Ulcers) (Fig. 4). This is important to keep in mind when examining the animal, because we may be able to identify different lesions which represent evolving stages of the disease or we may only find the final result of 112 S. Colombo VetBooks.ir Fig. 3 Retroauricular abscess in a stray cat Fig. 4 Hemorrhagic crust covering an erosion/ulcer on the nose of a cat with herpesvirus infection this process, which is the crust. Table 1 lists selected causes of papules, pustules, abscesses, crusts and furuncles in cats. Diagnostic Approach Signalment and History Contagious diseases such as notoedric mange and dermatophytosis are most commonly observed in kittens, while neoplasia is typically seen in older cats. Cutaneous abscesses occur more often in intact male cats, as a consequence of fighting. Breed may be a relevant point in the diagnostic approach: Persian cats are predisposed VetBooks.ir Papules, Pustules, Furuncles and Crusts Table 1 Selected causes of papules, pustules, furuncles, abscesses and crusts Papules Pustules Furuncles Abscess Crusts 113 Notoedric mange Dermatophytosis Mosquito-bite hypersensitivity Allergic diseases Urticaria pigmentosa-like dermatitis Xanthomas Mast cell tumor Pemphigus foliaceus Complicated chin acne Bacterial infections Trauma (including self-inflicted) Pyoderma Notoedric mange Dermatophytosis Subcutaneous and systemic fungal infections Herpesvirus dermatitis Poxvirus infection Allergic diseases Mosquito-bite hypersensitivity Adverse drug reactions Pemphigus foliaceus Complicated chin acne Perforating dermatitis Idiopathic facial dermatitis of Persian and Himalayan cats Squamous cell carcinoma Idiopathic/behavioral ulcerative dermatitis to dermatophytosis and idiopathic facial dermatitis [3]. Urticaria pigmentosa-like dermatitis has been described in Devon rex and Sphynx cats [1, 4]. History is obviously of paramount importance for the diagnosis when previous trauma (including self-induced) is suspected in a cat examined for a crusting lesion. Especially in kittens, detailed information on where the pet was acquired must always be collected. Being found as a stray or adopted from a cattery may represent a predisposing factor for dermatophytosis, notoedric mange and herpesvirus dermatitis. Lifestyle is also relevant, because outdoor cats may be affected by mosquito-bite hypersensitivity and development of abscesses more commonly than indoor cats. Regularly hunting mice and voles is a predisposing factor for Poxvirus infection. Contagion of in-contact pets or people should prompt investigation for dermatophytes and ectoparasites. Last but not least, one very important question to ask when taking the history is whether the cat is pruritic or not, and if pruritus is continuously present or seems to occur at a specific time of the year. Notoedric mange is a severely pruritic disease, and seasonal pruritus may suggest flea-bite or mosquito-bite hypersensitivity, and feline atopic syndrome. 114 S. Colombo VetBooks.ir Clinical Presentation Papules and pustules are in most cases multiple lesions, sometimes with a grouped configuration. In feline urticaria pigmentosa-like dermatitis, papules may have a linear configuration [1]. A single or many furuncles may be observed in chin acne. The distribution of papules, pustules, furuncles and crusts may be localized or generalized. The abscess is usually a single lesion. Papules and pustules are primary skin lesions; however, in most diseases, they represent one step in a pathological continuum of lesions. For example, although papules are the primary lesions in notoedric mange, they may not be visible, because they are covered by very thick crusts. Multiple, erythematous small papules covered by crusts, especially on the dorsum, may develop representing a feline-specific clinical presentation called miliary dermatitis [5, 6] (see later) (Fig. 5). The location of the lesions on the cat’s body may be helpful in developing a correct list of differential diagnoses (Table 2). An erythematous to hyperpigmented papular eruption, which may have a linear distribution on the ventrolateral chest and abdomen, is often pruritic and occurs in a Devon rex or Sphynx cats, is consistent with urticaria pigmentosa-like dermatitis (Fig. 6) [1, 4]. Small, erythematous, and crusted papules may suggest mosquito-bite hypersensitivity, when distributed on the dorsal nose, pinnae and footpads (Fig. 7) [7]. Pustules may be difficult to observe because they are transient, fragile lesions, but, when observed on the face, inner pinnae and abdomen, close to the nipples and on footpads should prompt investigation for pemphigus foliaceus (Fig. 8) [8]. Furuncles in cats are usually observed on the chin, where they develop when chin acne becomes complicated by secondary bacterial infection. A soft, fluctuant swelling, occasionally with a draining tract from which purulent exudate comes out, located on the face, neck, or tail base, most likely represents an abscess. Crusts are extremely common lesions, as they are the final result of the pathological continuum of lesions described in this chapter, as well as of traumatic lesions. Fig. 5 Miliary dermatitis in an allergic cat VetBooks.ir Papules, Pustules, Furuncles and Crusts Table 2 Common locations of papules, pustules, abscesses, crusts and furuncles in selected feline skin diseases Papules Distribution Head, pinnae, neck, paws, perineum Head, pinnae, paws, tail, generalized Head, pinnae, paws Rump Head, paws, bony prominence Pustules Head, pinnae, claw folds, abdomen Furuncles Chin Abscesses Neck, shoulders, tail base Crusts Site of previous trauma Face Face, ear canals Head, pinnae 115 Disease Notoedric mange Dermatophytosis Mosquito-bite hypersensitivity Flea-bite hypersensitivity Xanthomas Pemphigus foliaceus Complicated chin acne Bacterial infections Trauma Herpesvirus dermatitis Idiopathic facial dermatitis of Persian and Himalayan cats Squamous cell carcinoma Fig. 6 Multiple erythematous papules in a Devon rex cat with urticaria pigmentosa-like dermatitis One helpful clinical hint, when crusts are observed, is their color. If the crusts are dark brown, they are composed by dried blood and the lesion was most likely caused by a deep skin disease (ulcer) or (self-)trauma. If they are yellow, they represent dried purulent material and intact pustules should be carefully searched for. Very thick and dry light-colored crusts on the head, margins of pinnae, neck, paws, VetBooks.ir 116 S. Colombo Fig. 7 Papules on the pinna of a cat affected by mosquito-bite hypersensitivity and perineum, associated with severe pruritus, are the predominantly observed lesions in notoedric mange. Multiple, conical, very dry and thick crusted lesions (eschars) developing at sites of previous trauma may indicate a rare feline disease called acquired reactive perforating collagenosis or perforating dermatitis (Fig. 9) [9]. These lesions are difficult to remove and usually cover an ulcerated, hemorrhagic area. Pruritus and adherent, black, variably dried exudate covering areas of erythema or erosions distributed around the eyes, mouth, and chin are typical of idiopathic facial dermatitis of Persian and Himalayan cats, also called dirty face disease [3]. VetBooks.ir Papules, Pustules, Furuncles and Crusts 117 Fig. 8 Pustules and crusting on the inner pinna of a cat with pemphigus foliaceus Miliary Dermatitis Miliary dermatitis is a peculiar clinical presentation observed only in the cat. It is characterized by small, crusted papules “resembling millet seeds”, hence the name, which are more easily felt by touching through the haircoat then seen. Miliary dermatitis mainly affects the trunk and neck and is often associated with pruritus and selfinduced alopecia (Fig. 10) [5, 6]. Differential diagnoses of miliary dermatitis are listed in Table 3. Miliary dermatitis should be investigated following the diagnostic approach to pruritus (Chapter, Pruritus). VetBooks.ir 118 S. Colombo Fig. 9 Dry, thick, adherent yellow crust on the inner pinna of a young cat with perforating dermatitis Fig. 10 Alopecia and miliary dermatitis on the dorsum of a cat affected by flea-bite hypersensitivity Table 3 Differential diagnoses of miliary dermatitis Miliary dermatitis Cheyletiellosis Other ectoparasites (Lynxacarus radowski) Dermatophytosis Flea-bite hypersensitivity Adverse reaction to food Feline atopic syndrome Adverse drug reaction Pemphigus foliaceus Papules, Pustules, Furuncles and Crusts 119 VetBooks.ir Diagnostic Algorithm This section is illustrated in Fig. 11. Red squares with numbers represent the steps of the diagnostic process, explained below. 1 2 3 4 Consider signalment, history and physical examination Signalment, history, and physical examination may give the clinician extremely useful information for the diagnostic process. In a primarily outdoor intact male cat presenting with a fluctuant mass on the neck, for example, the most likely diagnosis is an abscess. When the main presenting signs are furuncles on the chin of a cat that suffers from chin acne, it is very likely that acne has become secondarily complicated by a bacterial infection. If physical examination reveals papules, pustules or crusts, a standardized sequence of diagnostic tests is usually required to make the diagnosis. Perform skin scrapings Skin scrapings must be performed whenever papules, pustules, crusts or furuncles are observed. Skin scrapings are diagnostic for notoedric mange and may identify Demodex cati mites in cases of chin furunculosis [10]. Perform Wood’s lamp examination and fungal culture These two diagnostic tests, taken together, are diagnostic for dermatophytosis or, if negative results are obtained, are helpful to rule it out. Since dermatophytosis may present with papules, pustules, miliary dermatitis and crusts in cats, a fungal culture is appropriate in all cases presenting with these lesions (Fig. 12). Perform cytology When the physical examination reveals the presence of an abscess, cytology from the purulent exudate should always be performed to support the diagnostic hypothesis. Usually, large numbers of degenerate neutrophils are visible, admixed with bacteria and variable numbers of macrophages, lymphocytes and plasma cells. To identify the bacteria species causing the abscess, bacterial culture and sensitivity testing should be performed. It is also advisable testing cats with abscesses for FIV and FeLV. Cytological examination of exudate draining from furuncles on the chin usually shows pyogranulomatous inflammation with bacteria. Bacterial culture and sensitivity testing for aerobes and anaerobes may be required to identify the causative microorganism and choosing the most effective antibiotic for treatment, if needed [2]. Papules, pustules and crusts should always be investigated by cytological examination, a simple test that often gives very useful information. The observation of large numbers of non-degenerate neutrophils admixed with many acantholytic keratinocytes suggests pemphigus foliaceus. Eosinophilic inflammation is very common in cats. If eosinophils are present in large numbers within a mixed inflammatory infiltrate in samples obtained from crusted, papular lesions on the bridge of the nose, mosquito-bite hypersensitivity is a likely diagnosis [7]. Skin scraping 6 Histopathology Miliary dermatitis History Pruritus Physical examination Papules Pustules Crusts 5 Signalment, History, Physical examination Fig. 11 Diagnostic algorithm to papules, pustules, furuncles, abscesses and crusts Herpesvirus dermatitis Poxvirus infection Subcutaneous and systemic fungal infections Adverse drug reactions Perforating dermatitis Idiopathic facial dermatitis of Persian and Himalayan cats 4 Cytology Fungal culture 3 Wood’s lamp examination Subcutaneous and systemic fungal infections Pemphigus foliaceus Mosquito-bite hypersensitivity Urticaria pigmentosa-like dermatitis Xanthomas Mast cell tumor Squamous cell carcinoma Dermatophytosis Notoedric mange 2 1 Skin scraping 4 Complicated chin acne Cytology Bacterial culture and sensitivity testing FIV-FeLV serology Go to chapter 9 Pruritus Chin acne and demodicosis 2 Furuncles Abscess Papules, Pustules, Furuncles, Abscess, Crusts VetBooks.ir 120 S. Colombo VetBooks.ir Papules, Pustules, Furuncles and Crusts 5 121 Neutrophils, eosinophils and occasionally mast cells observed in samples from erythematous, hyperpigmented papules on the skin of a Devon rex or Sphynx cat are suggestive of urticaria pigmentosa-like dermatitis [4]. Finally, cytological examination may show a monomorphic population of well-differentiated mast cells in mast cell tumors or epithelial cells in small aggregates or as single cells, with aspects of squamous differentiation, often admixed with neutrophils and other inflammatory cells, in squamous cell carcinomas (Fig. 13). Cytological findings obtained from crusting, papular or pustular lesions must always be confirmed by biopsy and histopathological examination. Consider history, pruritus and physical examination When skin scrapings, Wood’s lamp examination and fungal culture yield negative results and cytological findings are nonspecific (e.g., neutrophilic inflammation), one must carefully re-consider the history and clinical findings. In a continuously or seasonally pruritic cat, presenting with crusted papules on Fig. 12 Alopecia and crusting on the face of a cat with dermatophytosis Fig. 13 Hemorrhagic crusting on the nose of a cat with squamous cell carcinoma VetBooks.ir 122 6 S. Colombo the dorsum, or, less commonly, with generalized distribution, miliary dermatitis should be further investigated following the diagnostic approach to pruritus (Chapter, Pruritus). Take biopsies for histopathological examination Histopathological examination should always be performed if pemphigus foliaceus, mosquito-bite hypersensitivity, urticaria pigmentosa-like dermatitis, or infectious, metabolic and neoplastic diseases are suspected, based on cytological findings. Other diseases with nonspecific cytological findings and requiring histopathological examination for the diagnosis are, for example, viral diseases, perforating dermatitis, idiopathic facial dermatitis of Persian and Himalayan cats and adverse drug reactions. References 1. Vitale C, Ihrke PJ, Olivry T, Stannard AA. Feline urticaria pigmentosa in three related Sphinx cats. Vet Dermatol. 1996;7:227–33. 2. Jazic E, Coyner KS, Loeffler DG, Lewis TP. An evaluation of the clinical, cytological, infectious and histopathological features of feline acne. Vet Dermatol. 2006;17:134–40. 3. Bond R, Curtis CF, Ferguson EA, Mason IS, Rest J. An idiopathic facial dermatitis of Persian cats. Vet Dermatol. 2000;11:35–41. 4. Noli C, Colombo S, Abramo F, Scarampella F. Papular eosinophilic/mastocytic dermatitis (feline urticaria pigmentosa) in Devon rex cats: a distinct disease entity or a histopathological reaction pattern? Vet Dermatol. 2004;15:253–9. 5. Hobi S, Linek M, Marignac G, Olivry T, Beco L, Nett C, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 6. Diesel A. Cutaneous hypersensitivity dermatoses in the feline patient: a review of allergic skin disease in cats. Vet Sci. 2017:25. https://doi.org/10.3390/vetsci4020025. 7. Nagata M, Ishida T. Cutaneous reactivity to mosquito bites and its antigens in cats. Vet Dermatol. 1997;8:19–26. 8. Olivry T. A review of autoimmune skin diseases in domestic animals: I – superficial pemphigus. Vet Dermatol. 2006;17:291–305. 9. Albanese F, Tieghi C, De Rosa L, Colombo S, Abramo F. Feline perforating dermatitis resembling human reactive perforating collagenosis: clinicopathological findings and outcome in four cases. Vet Dermatol. 2009;20:273–80. 10. Beale K. Feline demodicosis: a consideration in the itchy or overgrooming cat. J Feline Med Surg. 2012;14:209–13. General References For definitions: Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 10 May 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Miller WH, Griffin CE, Muller CKL. Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Foster A, Rosenkrantz W. Veterinary allergy. Chichester: Wiley Blackwell; 2014. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Plaques, Nodules and Eosinophilic Granuloma Complex Lesions Silvia Colombo and Alessandra Fondati Abstract Plaques and nodules, including the lesions belonging to the eosinophilic granuloma complex (EGC), are common in cats. Plaques and nodules are caused in most cases by infectious, allergic, metabolic or neoplastic diseases. Clinical presentations of plaques and nodules and their preferential localization in selected feline diseases are described, together with useful hints coming from signalment and history. A feline-specific group of plaques or nodules, known as the EGC, and its specific features are also addressed in this chapter. EGC traditionally comprises eosinophilic plaque (EP), eosinophilic granuloma (EG) and lip (indolent) ulcer (LU). The diagnostic approach to plaques and nodules starts with the cytological examination, which may help the clinician to differentiate between the neoplastic and the inflammatory nature of the lesion. Histopathological examination is required to make or to confirm the diagnosis, and further testing is usually suggested by the histopathological diagnosis. Definitions A plaque is a flat elevation of the skin greater than 1 cm of diameter, and its size is, by definition, larger than its height. Plaques often form from a papule increasing in size or by coalescence of multiple papules. S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy A. Fondati Veterinaria Trastevere - Veterinaria Cetego, Roma, RM, Italy Clinica Veterinaria Colombo, Camaiore, LU, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_6 123 VetBooks.ir 124 S. Colombo and A. Fondati A nodule is a solid, palpable and circumscribed skin lesion greater than 1 cm of diameter. Nodules can be further characterized by their deepness, as epidermal, dermal or subcutaneous nodules. Nodules may open toward the skin surface and a draining tract may develop, with exudate of variable aspect and consistency coming out of the lesion. A peculiar type of nodule is the cyst, which is a cavity containing fluid or semisolid material lined by an epithelial wall. Both nodules and plaques may be described by adding features such as number, size, shape, color, consistency (e.g., hard or soft), surface changes (e.g., alopecic, eroded, ulcerated) and relationship with the surrounding tissues (e.g., fixed, movable). A soft, fluctuant, circumscribed nodule containing a collection of pus is called abscess, and is described in Chapter, Papules, Pustules, Furuncles and Crusts. Other relevant descriptors are whether the lesion is pruritic or non-pruritic and whether it is painful or painless. Plaques and nodules are common in cats and are the primary lesions of two of the clinical presentations of the eosinophilic granuloma complex (EGC). EGC traditionally comprises eosinophilic plaque (EP), eosinophilic granuloma (EG), and lip (indolent) ulcer (LU). These lesions affect the skin, lips and oral cavity of cats and have been initially grouped together because they were observed simultaneously on the same cat, therefore suggesting a common underlying cause. The EGC can be considered a “complex” in all respects, indeed, because EP, EG, and LU share clinical and histopathological aspects and a common etiopathogenesis, in which eosinophils play a pivotal role. Pathogenesis A plaque is a flat, solid lesion due to infiltration of inflammatory or neoplastic cells in the skin. In cats, it is most commonly associated with allergic or neoplastic diseases. It may develop because a papule increases in size or because many papules coalesce. In feline dermatology, the term plaque is most often used to describe the EP, a specific lesion belonging to the EGC (Fig. 1). Fig. 1 Eosinophilic plaque in a flea-allergic cat VetBooks.ir Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 125 EGC is not a definitive diagnosis. It should be rather considered a cutaneous reaction pattern most likely incited by underlying allergic causes, including hypersensitivity reactions to flea and, less commonly, environmental and food allergens. Occasionally, stings or bites of arthropods other than fleas might be considered as triggering factors for cutaneous eosinophil recruitment. However, in some cases, no external inciting stimuli can be identified and EGC lesions remain idiopathic. However, it must be taken into account that the reliability of current available diagnostic procedures does not always allow to definitely confirm/exclude hypersensitivity reactions towards environmental allergens in the cat. Based on observations of EGC in family-related cats, a genetic, inheritable “dysregulation” of the eosinophil response has been suggested to predispose to the development of EGC in the absence of detectable underlying causes, particularly in kittens. A combined genetic and allergic etiopathogenesis has been also suggested for EGC [1]. A genetic predisposition to develop intense eosinophil responses might help to explain why only a few cats develop EGC lesions, whereas the hypothesized underlying allergic stimuli are so largely distributed and more commonly associated with different reaction patterns, such as head and neck pruritus, self-induced alopecia or miliary dermatitis. On the other hand, a genetically based “abnormal” eosinophil response would not fit with clustering of cases in unrelated in-contact cats or with the lack of predisposition to develop extra-cutaneous eosinophilic diseases in cats suffering from EGC. Nodules also develop because of infiltration of inflammatory or neoplastic cells, however they are usually not flat and may extend deeper in the dermis and subcutaneous tissue. Non-neoplastic nodules may be induced by infectious agents, such as bacteria or fungi, or may be sterile, as it happens in EG or sterile nodular panniculitis. Uncommon causes of nodules or, rarely, plaques in cats are foreign bodies and deposition of calcium or lipids in the skin (Fig. 2) [2]. Cysts may be caused by congenital defects of development of different skin components or by obstruction of a sebaceous/apocrine duct (Fig. 3) [3]. Table 1 lists the most common causes of plaques and nodules in cats. Fig. 2 Nodule of calcinosis cutis on the chin of a cat with chronic kidney disease VetBooks.ir 126 S. Colombo and A. Fondati Fig. 3 Multiple cysts on the muzzle of a Persian cat with feline cystomatosis. (Courtesy of Dr. Stefano Borio) Table 1 Selected causes of plaques and nodules Plaques Eosinophilic plaque/granuloma Lip ulcer Papillomavirus infections Xanthomas Bowenoid in situ carcinoma Cutaneous lymphocytosis Mast cell tumor Progressive feline histiocytosis Nodules Botryomycosis Leprosy Rapidly growing mycobacterial infections Nocardiosis Dermatophytic mycetoma Eumycotic mycetomas Pheohyphomycosis Sporotrichosis Cryptococcosis Leishmaniosis Eosinophilic granuloma Calcinosis cutis Xanthomas Sterile granuloma/pyogranuloma syndrome Feline progressive histiocytosis Sterile nodular panniculitis Plasma cell pododermatitis Squamous cell carcinoma Basal cell tumors Follicular tumors Hemangiosarcoma Lymphangiosarcoma Mast cell tumor Sarcoid Vaccine-site fibrosarcoma Epitheliotropic/non-epitheliotropic cutaneous lymphoma Melanocytoma/melanoma Ceruminous cystomatosis Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 127 VetBooks.ir Diagnostic Approach Signalment and History Plaques and nodules are usually observed in adult or older cats and are due to infectious, allergic, metabolic or neoplastic diseases in the majority of cases. Nodular lesions with breed predisposition are dermatophytic mycetoma (Fig. 4) and apocrine cystomatosis, occurring more commonly in Persian cats, and mast cell tumor, being more often diagnosed in Siamese cats [4]. History should investigate the cat’s lifestyle, since most bacterial and fungal infections presenting with nodules require a penetrating wound to develop. For this reason, these diseases are more likely to occur in cats allowed to go outdoors. More specifically, contact with pigeon droppings has been advocated in cryptococcosis and contact with decaying plant material in sporotrichosis, while leprosy syndrome is usually reported in hunting or fighting cats [5, 6]. History of travelling or living in endemic areas may suggest diseases such as leishmaniosis, which occurs in specific geographic locations [7]. When a cat is presented for a nodular lesion, neoplastic diseases should always be included in the list of differential diagnoses. Useful information may be gathered by enquiring about the age and time of lesion development, changes in its appearance and size and concurrent systemic signs presented by the cat. Vaccinal history is also very relevant, because cats are predisposed to vaccination-site fibrosarcoma (Fig. 5) [8]. History of prolonged sun exposure in a white cat may suggest squamous cell carcinoma (Fig. 6). EGC lesions may be observed in cats of any breed, sex, and age; however, they frequently occur in young cats and occasionally appear in few month-old kittens. Lesions onset varies from acute (a few days) in EP to slow in LU and EG. Pruritus varies from intense in EP to variable in EG and absent in LU. If pruritus is absent and lesions are not clearly visible, as in selected cases of linear EG on caudal thighs, Fig. 4 Large nodule on the leg of a Persian cat affected by dermatophytic mycetoma VetBooks.ir 128 S. Colombo and A. Fondati Fig. 5 Relapse of vaccination-site fibrosarcoma in a cat Fig. 6 Large nodules diagnosed as squamous cell carcinoma on the dorsum of a congenitally alopecic cat lesions are usually identified by the owner when touching the cat (Fig. 7). Normally, EGC lesions are chronically persistent or recurrent, but, especially in kittens, EG may spontaneously regress with no further relapses. Clinical Presentation Plaques are, in most cases, lesions belonging to the EGC and may be single or more commonly multiple. Clinical features of the EGC, including EP, EG, and LU, have been well delineated and are considered quite distinctive [9]. The EP appears as intensely pruritic, oozing, eroded, firm, coalescing papules and plaques affecting sites accessible to being licked, such as ventral abdomen and inner thighs. Secondary bacterial infection and regional lymphadenopathy are common [10]. Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 129 VetBooks.ir Fig. 7 Linear granuloma on the hind limb of a cat EG classically occurs as firm, yellowish, variably pruritic, alopecic, erythematous and crusting papules and plaques with a striking linear configuration when affecting the caudal thigh. EG may also appear as single, yellowish papulo-nodular lesions located anywhere on the body, including paws, mid-lower lip/chin, lip commissure and oral cavity. Pedal EG lesions are frequently ulcerated and crusted whereas mucosal lesions appear as irregularly surfaced yellowish nodules, frequently located on the tongue and the palate. LU refers to an apparently non-pruritic and non-painful, reddish-brown to yellowish, glistening, non-bleeding, well-circumscribed, frequently concave ulcer with raised margins and the aspect of an ulcerated plaque rather than a true ulcer. The LU occurs most commonly on the midline of the upper lip, at the philtrum or adjacent to the upper canine tooth, mono- or bilaterally (Fig. 8). EGC lesions with overlapping features of more than one form are commonly observed and lesion definition can be difficult, as is the case of solitary or linearly grouped ulcerated EG resembling LU or EP. Lesions might be therefore described as papules, plaques and nodules belonging to the EGC, with no further clinical distinction. This observation raises the question on the adequacy of the currently 130 S. Colombo and A. Fondati VetBooks.ir Fig. 8 Bilateral ulcer on the upper lips Fig. 9 Single, erythematous, and exfoliative nodule on the front limb of a cat with epitheliotropic cutaneous lymphoma adopted nomenclature that represents a mixture of clinical (plaque and ulcer) and histologic (eosinophilic and granuloma) terms. Considering that the striking clinical phenotype of EGC consists of firm, raised papules, plaques and nodules and of sharply demarcated ulcers, the main clinical differential diagnoses include deep bacterial, including mycobacterial, or fungal infections and neoplasia. Specifically, the main differentials to be taken into account are squamous cell carcinoma for LU and mast cell tumor, cutaneous lymphocytosis, and cutaneous infiltration of mammary adenocarcinoma for EP. In xanthomas, plaques may be whitish-yellow in color, occasionally ulcerated and occurring on the head and extremities, while they can be hyperkeratotic and hyperpigmented in papillomas or Bowenoid in situ carcinoma [2, 11]. Erythematous, eroded, round plaques or nodules clinically indistinguishable from eosinophilic plaques may be observed in cutaneous lymphocytosis or epitheliotropic cutaneous lymphoma (Fig. 9) [12, 13]. VetBooks.ir Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 131 Nodules may be single or multiple. In terms of usefulness for the diagnosis, relevant clinical features of nodules are location (Table 2), consistency and presence or absence of draining tracts. Soft, fluctuant nodules draining exudate on the trunk may represent sterile nodular panniculitis or mycobacterial infection (Fig. 10). A nodule affecting the bridge of the nose and deforming the cat’s profile (roman nose) may suggest cryptococcosis or nasal lymphoma. Swelling of one or more footpads may indicate plasma cell pododermatitis (Fig. 11) [14]. Occasionally, nodules may drain an exudate containing macroscopically visible granules (grains). The grains are usually white in bacterial botryomycosis, yellow in dermatophytic mycetomas and of variable colors in eumycotic mycetomas [5]. A nodule in the Table 2 Common locations of plaques and nodules in selected feline skin diseases Plaques Distribution Head, extremities Abdomen, groin, axillae Nodules Abdomen, groin, rump Abdomen Head, extremities, tail base Dorsal nose Caudal thighs, chin, oral cavity, paws Paws Footpads Trunk Pinnae, eyelids, nasal planum Abdomen Interscapular, trunk Ear canals, pinnae Fig. 10 Fluctuant nodules with small ulcers and draining tract on the flank and rump due to mycobacterial infection (M. smegmatis) Disease Xanthomas Eosinophilic plaque Rapidly growing mycobacterial infections Nocardiosis Sporotrichosis Cryptococcosis Eosinophilic granuloma Calcinosis cutis Plasma cell pododermatitis Sterile nodular panniculitis Squamous cell carcinoma Lymphangiosarcoma Vaccine-site fibrosarcoma Ceruminous cystomatosis VetBooks.ir 132 S. Colombo and A. Fondati Fig. 11 Plasma cell pododermatitis with ulceration of the central metacarpal footpad interscapular region or dorsolateral thorax should raise suspicion of vaccine-site fibrosarcoma [8]. Multiple, grey-bluish nodules affecting the face and/or the ear canals and inner aspect of the pinnae may indicate ceruminous cystomatosis, particularly in Persian cats [3]. Diagnostic Algorithm This section is illustrated in Figs. 12a, b. Red squares with numbers represent the steps of the diagnostic process, explained below. 1 Perform cytology When the lesion is a nodule or a plaque, cytology is the first diagnostic test to perform during the consultation. Techniques useful to obtain samples for cytological examination from these lesions are fine needle insertion or aspiration and impression smears, if the nodule is ulcerated or if there is a draining tract. However, impression smears may be difficult to interpret in “open” lesions due to potential sample contamination. Cytology allows the clinician to differentiate between inflammatory and neoplastic infiltrates in most cases, and to select the most appropriate diagnostic tests to perform thereafter. When a monomorphous cell population with few or no inflammatory cells is observed, neoplasia should be suspected. Cytological examination allows to further characterize the cell population as composed by epithelial, mesenchymal, or round cells, and, in some cases, it may be diagnostic of a specific neoplasia (e.g., well-differentiated mast cell tumor). In the majority of cases, however, the lesion must be biopsied or excised to perform histopathological examination and properly “name” the tumor. Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 133 VetBooks.ir Plaques and nodules 1 Monomorphous cell population Neoplasia Epithelial cells 1 Mesenchymal cells Round cells 2 Non diagnostic Mast cell tumor ECL/NECL Cutaneous lymphocytosis Melanocytoma Melanoma Fibrosarcoma Hemangiosarcoma Lymphangiosarcoma Sarcoid 3 IHC Molecular techniques 3 Calcium salts Papillomavirus infections Histopathology Squamous cell carcinoma Basal cell tumor Follicular tumor Ceruminous cystomatosis IHC Mixed cell population Inflammation Plaques and nodules 2 Cytology 3 IHC Molecular techniques 3 Complete blood count Biochemistry Urinalysis Toluidine blue IHC Clonality testing Calcinosis cutis Plaques and nodules 2 Monomorphous cell population Neoplasia Plaques and nodules 1 Plasma cell pododermatitis 1 Cytology Mixed cell population Inflammation Lymphoplasmacellular inflammation Eosinophilic inflammation Pyogranulomatous/granulomatous inflammation Suspect: Leprosy Cryptococcosis Sporotrichosis Leishmaniosis Pheophyphomycosis With etiological agent Suspect: Botryomycosis Nocardiosis Dermatophytic mycetoma Eumycotic mycetoma Histopathology 3 Gram stain Acid fast stains PCR Bacterial culture Bacterial culture and sensitivity testing Botryomycosis Nocardiosis Go to chapter 9 Pruritus Without etiological agent With grains 2 3 Eosinophilic plaque Eosinophilic granuloma Sterile nodular panniculitis Sterile granuloma/pyogranuloma syndrome Rapidly growing mycobacteria Leprosy 4 3 Special stains for fungi Fungal culture IHC PCR Cryptococcosis Sporotrichosis Dermatophytic mycetoma Eumycotic mycetoma Pheophyphomycosis Complete blood count Biochemistry Urinalysis Serology Xanthomatosis Leishmaniosis Fig. 12 Diagnostic algorithm of plaques, nodules, and eosinophilic granuloma complex lesions 4 VetBooks.ir 134 2 S. Colombo and A. Fondati A mixed cell population observed on cytology indicates inflammation. Inflammatory cells most commonly identified include neutrophils, eosinophils, macrophages, lymphocytes, plasma cells and mast cells, often accompanied by a variable amount of red blood cells. The relative percentage of one cell type in respect to other inflammatory cells is used in cytology to define the different types of inflammation, such as pyogranulomatous (neutrophils and macrophages in variable proportions, epithelioid macrophages and giant histiocytic cells), granulomatous (same as before, with very few or no neutrophils), eosinophilic and lymphoplasmacellular inflammation. Etiological agents such as bacteria, fungi, and parasites can also be detected, as well as calcium salts in calcinosis cutis due to chronic kidney disease. Depending on the type of inflammation and the microorganism(s) observed, a diagnosis can be made in some cases. For example, amastigotes of the genus Leishmania in the cytoplasm of macrophages indicate leishmaniosis, or yeasts of the genus Cryptococcus within pyogranulomatous inflammation are suggestive of cryptococcosis. When the same type of inflammation is observed with unstained, rod-shaped bacteria within macrophages, mycobacterial diseases should be suspected. Whenever the exudate contains grains, cytology from a squashed grain may be useful: filamentous bacteria may suggest nocardiosis, while cocci or rods may point toward a diagnosis of bacterial botryomycosis. If grains appear amorphous and hyphae are detected at the periphery of a grain, dermatophytic mycetoma or eumycotic mycetoma are likely diagnoses. All these diagnoses should be confirmed by histopathological examination and cultures from biopsy samples. Histopathology and culture are also mandatory in all the cases in which cytology reveals granulomatous or pyogranulomatous inflammation without evidence of etiological agents. A predominantly eosinophilic inflammation together with characteristic clinical findings points toward a lesion of the EGC, while lymphoplasmacellular inflammation suggests plasma cell pododermatitis. In case of EGC lesions, the diagnostic workup is irrespective of the clinical form, the distribution of the lesions, and the presence or absence of pruritus (Fig. 9b). Histopathological examination may be performed to confirm the diagnosis. Cytological examination may also be non-diagnostic, because too few cells are obtained or the sample is heavily contaminated by blood. In ceruminous cystomatosis, for example, a clear fluid containing variable numbers of macrophages can be obtained. In these cases, histopathological examination must be carried out. Take biopsies for histopathological examination Histopathological examination is mandatory whenever a neoplastic disease is suspected. However, a non-neoplastic nodule or plaque also requires, in the majority of cases, histopathological examination to make or confirm the diagnosis and suggest further diagnostic tests. It must be remembered that the histological appearance of EGC lesions does not always reflect the clinical form and the eosinophilic infiltrate density is quite variable. LU, for instance, is commonly reported as a neutrophilic fibrosing dermatitis rather than an eosinophilic dermatitis. A progression of histological lesions has been described from a dermal VetBooks.ir Plaques, Nodules and Eosinophilic Granuloma Complex Lesions 3 4 135 eosinophilic infiltrate to fibrosis and neutrophilic ulceration, in a few months, in the LU of the upper lip. These findings might help to explain why LU is infrequently described as an eosinophil-rich dermatitis. Being clinicians reluctant to biopsy the cat’s lip, the majority of LU lesions might be present for months at the time they are histologically examined. In fact, LU are mostly biopsied to rule out neoplasia rather than to confirm the diagnosis of EGC. When collecting biopsy samples, some fresh tissue, preferably from the deep portion of the samples, should be stored in a sterile tube and frozen for possible microbial culture, molecular studies or both. Histopathological examination may be diagnostic for neoplasia or, in difficult cases, additional testing may be needed. Depending on the type of tumor identified or suspected on histopathological examination, special stains (e.g., toluidine blue or Giemsa for mast cell tumor), immunohistochemistry, or clonality testing (to differentiate cutaneous lymphocytosis from epitheliotropic cutaneous lymphoma) may be suggested by the pathologist to make the diagnosis. Special staining, immunohistochemistry and molecular techniques such as polymerase chain reaction (PCR) may also be useful to identify or characterize infectious agents which are difficult to see on “standard” histopathology or to grow on culture. Gram stain is useful to identify bacteria, while acid fast stains such as Ziehl-Neelsen may be necessary to visualize mycobacteria. Periodicacid of Schiff (PAS) stain is commonly used to identify fungi in tissues. Immunohistochemistry, PCR and/or other molecular techniques may be applied to diagnose papillomavirus infections, mycobacterial diseases and some uncommon fungal infections (pheohyphomycosis). If a deep bacterial or fungal infection is suspected, tissue cultures are recommended to identify the causative microorganisms. Cultures should be preferably performed in specialized Veterinary Labs, and clinicians should inform of the clinical suspicion. In selected cases, sensitivity testing can help to choose the correct antimicrobial treatment. A negative result, together with compatible clinical and histopathological findings, confirms the diagnosis in sterile diseases such as sterile nodular panniculitis and sterile granuloma/pyogranuloma syndrome. Perform complete blood count, biochemistry, urinalysis, and serology Complete blood count, biochemistry, and urinalysis are useful when a metabolic disease such as xanthomas or calcinosis cutis due to renal failure is suspected, based on the results of histopathological examination. If results of cytology and/or histopathology suggest a diagnosis of leishmaniosis, serology should also be performed. FIV and FeLV serology should be also carried out, especially in cats affected by infectious diseases. References 1. Colombini S, Clay Hodgin E, Foil CS, Hosgood G, Foil LD. Induction of feline flea allergy dermatitis and the incidence and histopathological characteristics of concurrent lip ulcers. Vet Dermatol. 2001;12:155–61. VetBooks.ir 136 S. Colombo and A. Fondati 2. Vogelnest LJ. Skin as a marker of general feline health: cutaneous manifestations of systemic disease. J Feline Med Surg. 2017;19:948–60. 3. Chaitman J, Van der Voerdt A, Bartick TE. Multiple eyelid cysts resembling apocrine hidrocystomas in three Persian cats and one Himalayan cat. Vet Pathol. 1999;36:474–6. 4. Moriello KA, Coyner K, Paterson S, Mignon B. Diagnosis and treatment of dermatophytosis in dogs and cats. Clinical consensus guidelines of the world association for veterinary dermatology. Vet Dermatol. 2017;28:266–e68. 5. Backel K, Cain C. Skin as a marker of general feline health: cutaneous manifestations of infectious disease. J Feline Med Surg. 2017;19:1149–65. 6. Gremiao IDF, Menezes RC, Schubach TMP, Figueiredo ABF, Cavalcanti MCH, Pereira SA. Feline sporotrichosis: epidemiological and clinical aspects. Med Mycol. 2015;53:15–21. 7. Pennisi MG, Cardoso L, Baneth G, Bourdeau P, Koutinas A, Mirò G, Oliva G, Solano- Gallego L. LeishVet update and recommendations on feline leishmaniosis. Parasit Vectors. 2015;8:302–20. 8. Hartmann K, Day MJ, Thiry E, Lloret A, Frymus T, Addie D, Boucraut-Baralon C, Egberink H, Gruffydd-Jones T, Horzinek MC, Hosie MJ, Lutz H, Marsilio F, Pennisi MG, Radford AD, Truyen U, Möstl K. Feline injection-site sarcoma: ABCD guidelines on prevention and management. J Feline Med Surg. 2015;17:606–13. 9. Buckley L, Nuttall T. Feline eosinophilic granuloma complex(ities) some clinical clarification. J Feline Med Surg. 2012;14:471–81. 10. Wildermuth BE, Griffin CE, Rosenkrantz WS. Response of feline eosinophilic plaques and lip ulcers to amoxicillin trihydrate–clavulanate potassium therapy: a randomized, double-blind placebo-controlled prospective study. Vet Dermatol. 2011;23:110–e25. 11. Munday JS. Papillomaviruses in felids. Vet J. 2014;199:340–7. 12. Gilbert S, Affolter VK, Gross TL, Moore PF, Ihrke PJ. Clinical, morphological and immunohistochemical characterization of cutaneous lymphocytosis in 23 cats. Vet Dermatol. 2004;15:3–12. 13. Fontaine J, Heimann M, Day MJ. Cutaneous epitheliotropic T-cell lymphoma in the cat: a review of the literature and five new cases. Vet Dermatol. 2011;22:454–61. 14. Dias Pereira P, Faustino AMR. Feline plasma cell pododermatitis: a study of 8 cases. Vet Dermatol. 2003;14:333–7. Further Readings “Plaque, nodule”. Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 31 Jan 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin diseases of the dog and cat. Clinical and histopathologic diagnosis. 2nd ed. Oxford: Blackwell Publishing; 2005. Miller WH, Griffin CE, Muller CKL. Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Excoriations, Erosions and Ulcers Silvia Colombo Abstract Excoriations, erosions and ulcers are relatively common lesions in the cat, and in general, they are quite non-specific. Excoriations are, by definition, self-induced lesions due to scratching, while erosions and ulcers develop spontaneously. Full thickness skin wounds are very suggestive of cutaneous asthenia or acquired skin fragility syndrome, depending on the cat’s age. Erosions and ulcers are often secondarily infected and may appear more severe because of pruritus due to infection. A peculiar feline clinical presentation, common in allergic diseases, is “head and neck pruritus,” with excoriations and ulcers being self-induced. This presentation is usually investigated following the diagnostic approach to pruritus. The most relevant clinical feature of erosions and ulcers is their location, which may be helpful for the diagnosis. In general, histopathology is the most important diagnostic test to make a specific diagnosis in erosive/ulcerative feline skin diseases. Definitions An excoriation is a superficial abrasion of the epidermis that results from scratching, or, less commonly, from licking or biting. It is a self-induced lesion and may show a linear pattern, directly reflecting its pathogenesis. An erosion is a superficial, moist, circumscribed lesion that results from loss of a part or all of the epidermis and does not involve the dermis. An erosion does not bleed and heals without scarring. An ulcer is a circumscribed skin defect in which the epidermis and at least the superficial dermis have been lost, and it is deeper than the erosion. The ulcer involves S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_7 137 VetBooks.ir 138 S. Colombo also the adnexa and may heal with scarring. Further features used to describe an ulcer relate to its margins, surface and presence of exudate eventually covering its bottom. The margins, for example, may be thickened, regular or irregular, and the bottom may be clean, hemorrhagic or necrotic. There may be a crust or purulent exudate covering the ulcerated area. Erosion and ulcer are difficult to be differentiated clinically, because the depth of a skin defect can only be defined with certainty by histopathological examination. For this reason, when describing a typical lesion or a disease, the words erosive and ulcerative are always used together. Pathogenesis The pathogenetic mechanisms underlying the formation of erosions and ulcers vary from external trauma, to congenital defects causing reduced skin resistance, to direct infectious or autoimmune damage to the skin. Erosions and ulcers are, in the vast majority of cases, complicated by self-induced trauma due to pruritus and/ or by secondary infections. The clinical appearance of any erosive and ulcerative disease may therefore evolve, and lesions may become deeper and more severe. A peculiar feline clinical presentation, common in allergic diseases, is ulceration due to “head and neck pruritus” (Fig. 1) [1]. Cats scratch using their hind paws and claws and may cause severe and extensive ulcers to these locations. Despite its name, the feline-specific lesion known as “indolent ulcer” or “lip ulcer” (Fig. 2) is an ulcerated plaque and is described in Chapter, Plaques, Nodules and Eosinophilic Granuloma Complex Lesions [2]. Fig. 1 Head and neck pruritus in an allergic cat VetBooks.ir Excoriations, Erosions and Ulcers 139 Fig. 2 Severe, bilateral indolent ulcer with necrotic material in the center In diseases such as cutaneous asthenia or acquired skin fragility syndrome, full thickness lacerations and skin detachment occur following minor trauma, and the lesions should be better described as wounds. Table 1 lists selected causes of excoriations, erosions and ulcers in cats. Diagnostic Approach Signalment and History Erosive/ulcerative skin diseases such as cutaneous asthenia and dystrophic or junctional epidermolysis bullosa are congenital and present at birth or shortly thereafter [3, 4]. In other cases, the disease has a delayed onset but is clinically apparent in young adult cats of specific breeds (idiopathic facial dermatitis of Persian and Himalayan cats, ulcerative nasal dermatitis of Bengal cats) [5, 6]. Full thickness wounds following minor trauma may occur in senior to geriatric cats in acquired skin fragility syndrome, which may be caused by hyperadrenocorticism (Fig. 3) or other diseases [7, 8]. Traumatic excoriations or wounds may be seen more often in tomcats, while neoplastic diseases are more common in older cats. History is very relevant for the diagnosis of feline erosive/ulcerative diseases. Previous or concurrent respiratory clinical signs may suggest herpesvirus dermatitis, while an outdoor lifestyle may predispose the cat to trauma, deep bacterial, mycobacterial or fungal infections, or, in white cats, to squamous cell carcinoma (Fig. 4) [9, 10]. Previous or concurrent drug administration should prompt the clinician to include adverse drug reactions and toxic epidermal necrolysis among the differential diagnoses, particularly if the lesions have a sudden onset [11]. Finally, the presence of pruritus may be a relevant information as it may be typical of some 140 S. Colombo Table 1 Selected causes of excoriations, erosions and ulcers VetBooks.ir Excoriations Erosions/ulcers Self-trauma Herpesvirus dermatitis Leprosy Rapidly growing mycobacterial infections Subcutaneous fungal infections Systemic fungal infections Myiasis Leishmaniosis Head and neck pruritusa (Table 3) Adverse drug reactions Pemphigus foliaceus Pemphigus vulgaris Vesicular diseases of the dermo-epidermal junction Erythema multiforme Toxic epidermal necrolysis Vasculitis Hyperadrenocorticism/acquired skin fragility syndrome Idiopathic facial dermatitis of Persian and Himalayan cats Ulcerative nasal dermatitis of Bengal cats Junctional/dystrophic epidermolysis bullosa Cutaneous asthenia Trauma Indolent ulcerb Idiopathic/behavioral ulcerative dermatitis Plasma cell pododermatitis Squamous cell carcinoma Chapter, Pruritus Chapter, Plaques, Nodules and Eosinophilic Granuloma Complex Lesions a b Fig. 3 Full thickness skin wound in a geriatric cat with hyperadrenocorticism VetBooks.ir Excoriations, Erosions and Ulcers 141 Fig. 4 Squamous cell carcinoma involving the lower eyelid and nose of a white cat diseases such as idiopathic/behavioral ulcerative dermatitis and of the clinical pattern described as “head and neck pruritus” [1, 12]. However, one must remember that pruritus may also be due to secondary infections of the erosion/ulcer. Clinical Presentation Erosions and ulcers are relatively common lesions in the cat and are quite non- specific. Accompanying primary or secondary lesions are uncommon, with the exception of crusts covering the erosions/ulcers. Nodules and plaques may have an eroded or ulcerated surface, as it happens in indolent ulcer and eosinophilic plaque. On the other hand, full thickness wounds are very specific once a traumatic etiology has been ruled out. Skin tears with minimal or no bleeding, occurring following minor traction, suggest cutaneous asthenia or acquired skin fragility syndrome, depending on the patient’s age [3, 7, 8, 13]. The concurrent presence of skin hyperextensibility is a feature of cutaneous asthenia, while thin, irregular scars represent resolved lesions and may be observed in both conditions. The most useful clinical features of erosions/ulcers are the lesions’ location (Table 2) and the presence or absence of pruritus. The face is the most common site for erosions/ulcers due to herpesvirus (Fig. 5) or calicivirus infections, occasionally with oral cavity involvement [9, 10]. Idiopathic facial dermatitis of Persian and Himalayan cats is initially characterized by an accumulation of adherent black material around the eyes, nose and mouth, and inflamed, eroded/ulcerated skin lesions underneath the exudate develop with time [5]. These lesions may be severely pruritic and secondary infections are common. Multiple erosions/ulcers, covered by crusts, on the tip of the pinnae, eyelids and/or nasal planum of a white cat should prompt the clinician to investigate squamous cell carcinoma. A hyperkeratotic, scaly, occasionally ulcerated nasal planum in Bengal cats has been reported and is thought to be a congenital disease [6]. Application of spot-on products to prevent 142 S. Colombo VetBooks.ir Table 2 Common locations of erosions/ulcers in selected feline skin diseases Distribution Oral cavity Abdomen, groin Upper lip Dorsal neck Footpads Trunk Nasal planum Muzzle Pinnae Eyelids Fig. 5 Large erosion/ulcer on the muzzle of a cat with herpesvirus infection Disease Herpesvirus dermatitis Pemphigus vulgaris Vesicular diseases of the dermo-epidermal junction Rapidly growing mycobacterial infections Eosinophilic plaques Indolent ulcer Adverse drug reaction (spot-on, injection) Idiopathic/behavioral ulcerative dermatitis “Head and neck pruritus” Plasma cell pododermatitis Hyperadrenocorticism Acquired skin fragility syndrome Ulcerative nasal dermatitis of Bengal cats Squamous cell carcinoma Pemphigus foliaceus Idiopathic facial dermatitis of Persian and Himalayan cats Pemphigus foliaceus Herpesvirus dermatitis “Head and neck pruritus” Squamous cell carcinoma Pemphigus foliaceus Squamous cell carcinoma Pemphigus vulgaris Vesicular diseases of the dermo-epidermal junction VetBooks.ir Excoriations, Erosions and Ulcers 143 ectoparasites may cause erosions/ulcers on the dorsal neck. Ulcerative lesions and draining tracts discharging exudate on the abdomen may be observed in rapidly growing mycobacterial infections [10]. Severely swollen, ulcerated metacarpal and/ or metatarsal footpads are suggestive of plasma cell pododermatitis [14]. In erythema multiforme, maculopapular lesions evolving to erosions/ulcers and crusts usually present with a generalized distribution [11]. ead and Neck Pruritus H Pruritus and self-induced erosions/ulcers involving the head, pinnae and neck are commonly observed and represent a peculiar clinical presentation in the feline species [1]. Variably sized erosions and ulcers are caused by the cat’s scratching with the hind paws, and the owner is usually well aware of the cat’s pruritus. These lesions may be very severe, secondary infections are often present, and their depth may reach the subcutis (Fig. 6). Other feline presentations typically observed in pruritic skin diseases, such as miliary dermatitis and self-induced alopecia, may be concurrently observed. Differential diagnoses of head and neck pruritus are listed in Table 3. Head and neck pruritus should be investigated following the diagnostic approach to pruritus (Chapter, Pruritus). Idiopathic/behavioral ulcerative dermatitis (Fig. 7), which presents as a very severe and extremely pruritic, usually single crusted ulceration affecting the dorsal neck, deserves a specific comment, since its etiopathogenesis is controversial. Suggested causes of idiopathic ulcerative dermatitis involve allergic diseases, Fig. 6 Very severe erosions/ulcers in a food allergic cat VetBooks.ir 144 S. Colombo Table 3 Differential diagnoses of head and neck pruritus Disease Herpesvirus dermatitis Dermatophytosis Notoedric mange Otodectic mange Demodicosis (Demodex gatoi) Trombiculiasis Lynxacarus infestation Flea-bite hypersensitivity Adverse reaction to food Feline atopic syndrome Mosquito-bite hypersensitivity Adverse drug reaction Pemphigus foliaceus Idiopathic facial dermatitis of Persian and Himalayan cats Idiopathic/behavioral ulcerative dermatitis Fig. 7 Idiopathic/ behavioral ulcerative dermatitis on the dorsal neck secondary infections, neurological diseases and a behavioral disorder, although most cases, as the name suggests, are idiopathic [12]. Diagnostic Algorithm This section is illustrated in Fig. 8. Red squares with numbers represent the steps of the diagnostic process, as explained below. 1 Consider history and clinical examination. When examining a cat with erosions/ulcers, the first step is to separate these lesions from full thickness wounds or skin lacerations following minor trauma, Excoriations, Erosions and Ulcers 145 VetBooks.ir Erosions and ulcers History and clinical examination 1 Full thickness wound Head and neck pruritus Indolent ulcer Monomorphous cell population Neoplasia Cytology Mixed cell population Inflammation 2 3 Histopathology Histopathology 3 Trauma Myasis Non diagnostic Neutrophilic inflammation, erythrocytes Acquired skin fragility syndrome Cutaneous asthenia Neutrophilic inflammation Acantholytic cells Pyogranulomatous/granulomatous inflammation Lymphoplasmacellular inflammation Squamous cell carcinoma Epitheliotropic cutaneous lymphoma 3 Histopathology 3 Histopathology Plasma cell pododermatitis Pemphigus foliaceus Vesicular diseases of the dermo-epidermal junction Adverse drug reaction Erythema multiforme Toxic epidermal necrolysis Idiopathic facial dermatitis of Persian and Himalayan cats Ulcerative nasal dermatitis of Bengal cats Junctional/dystrophic epidermolysis bullosa 4 Complete blood count Biochemistry Urinalysis Endocrinology testing X-ray Ultrasound TC/MRI (if appropriate) Leprosy Rapidly growing mycobacterial infections Subcutaneous fungal infections Systemic fungal infections Leishmaniosis 4 Complete blood count Biochemistry Urinalysis Serology PCR Go to chapter 9 Pruritus Leishmaniosis Special stains Fungal culture Bacterial culture IHC PCR 5 Leprosy Rapidly growing mycobacterial infections Subcutaneous fungal infections Systemic fungal infections Fig. 8 Diagnostic algorithm of erosions and ulcers 2 such as manual traction. Extreme fragility of the skin only occurs in two conditions, in cats. The first one is cutaneous asthenia, clinically apparent in kittens or young cats, while the second one occurs in old felines and gathers different diseases under the name “acquired skin fragility syndrome” [3, 7, 8, 13]. History would also help us, in most cases, to decide if the wound occurred following a major trauma such as a car accident. The presence of insect larvae in the wound indicates myiasis. If the cat is pruritic on the head and neck, or the main lesion is the “indolent” lip ulcer or an eroded plaque (Chapter, Plaques, Nodules and Eosinophilic Granuloma Complex Lesions), particularly when associated with self-induced alopecia, one should follow the diagnostic approach to pruritus, described in Chapter, Pruritus. Perform cytology. Cytologic examination of erosions/ulcers is often disappointing, because in most cases one can only observe non-specific findings, such as red blood cells and neutrophils. When neutrophils are present admixed with acantholytic cells, the main clinical suspicion is pemphigus foliaceus (Fig. 9). If a mixed cell population comprising large numbers of plasma cells and lymphocytes are observed and the cytology sample comes from a footpad, the diagnosis is plasma cell pododermatitis [14]. Eosinophils may be observed on samples taken from the tiny erosions underneath the crusts in miliary dermatitis, or from the eroded surface of an eosinophilic plaque. Pyogranulomatous inflammation is also a non- specific VetBooks.ir 146 S. Colombo Fig. 9 Pemphigus foliaceus in a domestic short-haired cat 3 4 5 c ytological picture; however, it is more commonly observed in infectious diseases such as mycobacterial or fungal infections and leishmaniosis. O ccasionally, a monomorphous cell population is seen on cytology, and this finding may suggest a neoplastic disease. Perform histopathology. Histopathology is of paramount importance in erosive/ulcerative feline skin diseases. First of all, it can confirm the diagnosis of neoplasia and acquired skin fragility syndrome. In cutaneous asthenia, histopathological comparison with a skin sample obtained from a cat of the same age and from the same site may be required, as well as special stains and electron microscopy. The majority of autoimmune, immune-mediated and idiopathic erosive/ulcerative skin diseases can be diagnosed by histopathology. In case of infectious diseases, a standard histopathological examination (hematoxylin-eosin, H&E) is in most cases only indicative, due to the difficulty of identifying the etiological agent without further diagnostic procedures, such as special stains or immunohistochemistry. Perform blood testing, serology, urinalysis and diagnostic imaging. In an old cat presenting with full thickness wounds and a histopathological diagnosis of acquired skin fragility syndrome, it is necessary to identify the causative disease in order to attempt a treatment. Skin fragility syndrome is often caused by hyperadrenocorticism; however, severe cachexia, diabetes mellitus, hepatic lipidosis or inflammatory and neoplastic diseases affecting the liver, nephrosis and some infectious diseases have all been reported [8, 13]. When history, clinical examination and histopathology suggest leishmaniosis, the diagnostic process should be completed by complete blood count, biochemistry, urinalysis, serology and/or PCR [10]. As said before, standard histopathology (H&E staining) may in some cases be suggestive of an infectious disease, without confirming a specific diagnosis. In these cases, further testing is mandatory and special stains (PAS for fungi, Ziehl-Neelsen for acid-fast bacteria, immunohistochemistry for leishmania and viruses), cultures and PCR should be requested depending on the case. Excoriations, Erosions and Ulcers 147 VetBooks.ir References 1. Hobi S, Linek M, Marignac G, Olivry T, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 2. Buckley L, Nuttall T. Feline Eosinophilic Granuloma Complex(ITIES): some clinical clarification. J Fel Med Surg. 2012;14:471–81. 3. Hansen N, Foster SF, Burrows AK, Mackie J, Malik R. Cutaneous asthenia (Ehlers–Danlos- like syndrome) of Burmese cats. J Feline Med Surg. 2015;17:954–63. 4. Medeiros GX, Riet-Correa F. Epidermolysis bullosa in animals: a review. Vet Dermatol. 2015;26:3–e2. 5. Bond R, Curtis CF, Ferguson EA, Mason IS, Rest J. An idiopathic facial dermatitis of Persian cats. Vet Dermatol. 2000;11:35–41. 6. Bergvall K. A novel ulcerative nasal dermatitis of Bengal cats. Vet Dermatol. 2004;15:28. 7. Boland LA, Barrs VR. Peculiarities of feline hyperadrenocorticism: update on diagnosis and treatment. J Feline Med Surg. 2017;19:933–47. 8. Furiani N, Porcellato I, Brachelente C. Reversible and cachexia-associated feline skin fragility syndrome in three cats. Vet Dermatol. 2017;28:508–e121. 9. Hargis AM, Ginn PE. Feline herpesvirus 1-associated facial and nasal dermatitis and stomatitis in domestic cats. Vet Clin North Am Small Anim Pract. 1999;29(6):1281–90. 10. Backel K, Cain C. Skin as a marker of general feline health: cutaneous manifestations of infectious disease. J Feline Med Surg. 2017;19:1149–65. 11. Yager JA. Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis: a comparative review. Vet Dermatol. 2014;25:406–e64. 12. Titeux E, Gilbert C, Briand A, Cochet-Faivre N. From feline idiopathic ulcerative dermatitis to feline behavioural ulcerative dermatitis: grooming repetitive behaviors indicators of poor welfare in cats. Front Vet Sci. 2018; https://doi.org/10.3389/fvets.2018.00081. 13. Vogelnest LJ. Skin as a marker of general feline health: cutaneous manifestations of systemic disease. J Feline Med Surg. 2017;19:948–60. 14. Dias Pereira P, Faustino AMR. Feline plasma cell pododermatitis: a study of 8 cases. Vet Dermatol. 2003;14:333–7. General References For definitions: Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 10 May 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Miller WH, Griffin CE, Campbell KL. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Scaling Silvia Colombo Abstract Exfoliative diseases in cats are clinically characterized by dry or greasy scaling and, less commonly, by follicular casts. In normal skin, there is a continuous turnover of cells, with new keratinocytes being produced in the basal layer and migrating upward to become non-nucleated corneocytes in the stratum corneum. Corneocytes are shed in the environment and are not visible to the naked eye. When this process is abnormal, scales become macroscopically visible. The most common cause of scaling in cats is poor grooming, usually associated with older age, obesity or concurrent systemic diseases. Greasy scaling is often associated with Malassezia overgrowth, while follicular casts are rare in the feline species. The diagnostic approach involves ruling out ectoparasitic diseases and dermatophytosis, evaluating the presence or absence of Malassezia spp. by cytology, and assessing the cat’s general health status, especially in older patients. Histopathology is usually required to make the diagnosis of the majority of exfoliative dermatoses. Definitions A scale is a small, thin, dry piece of cornified layer detaching from the skin, and scaling is the process of shedding scales. In English, scale and squame as well as scaling, desquamation and exfoliation are synonyms and are used indifferently. The informal term used to describe scaling is dandruff. In normal conditions, exfoliation occurs continuously, without the formation of visible scaling. Desquamation becomes visible when it occurs in increased amount, because the epidermal differentiation is abnormal. S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_8 149 VetBooks.ir 150 S. Colombo Scales may be further characterized as dry or greasy, and their color may be white, silver, yellow, brown or grey, depending on the causative disease. Dry scaling is common in cats, while greasy scaling is observed only in a few skin diseases. Scales are also often described as pityriasiform, which means small, thin, whitish and similar to oat bran, or psoriasiform, a term used to describe larger, thicker and often silvery scales. Scales arranged in a circle are described as an epidermal collarette and are rarely observed in cats. The epidermal collarette is the final evolutive stage of a papule or a pustule (Chapter, Papules, Pustules, Furuncles and Crusts). A follicular cast is an accumulation of keratin and follicular content which adheres to the hair shaft, protruding from the follicular ostium. This material often glues together a tuft of hair or may accumulate around a single hair shaft. Follicular casts are very uncommon in cats but may represent a useful clinical hint toward the diagnosis. Pathogenesis In the normal skin, there is a continuous turnover of cells, with new keratinocytes being produced in the basal layer, maturing in the spinous layer, and dying to become corneocytes in the horny layer. Corneocytes are shed in the environment and are not visible to the naked eye. In abnormal situations, scaling becomes obvious because the corneocytes detach in larger clusters. This may be due to increased production or reduced shedding of the horny layer or to abnormalities of the superficial lipid film, that covers and protects the skin surface. An increased production of the horny layer may occur in congenital diseases such as ichthyosis or primary seborrhea; however, these conditions are extremely rare in cats [1]. More commonly, the increased thickness of the horny layer is a response to an external insult, such as sunrays damage in solar dermatitis (Fig. 1), which may evolve into actinic keratosis and squamous cell carcinoma, or to ectoparasites feeding on the skin surface in cheyletiellosis. Another pathogenetic mechanism underlying scaling dermatoses is the infiltration of inflammatory or neoplastic cells in the skin, as it happens in erythema multiforme (Fig. 2), exfoliative dermatitis with/without thymoma or epitheliotropic cutaneous lymphoma [2–4]. In cats, reduced shedding of horny layer is usually due to poor grooming, more commonly in older or obese cats or in cats affected by systemic diseases such as diabetes mellitus or hyperthyroidism. The lipid film that protects the skin is, at least in part, produced by the sebaceous glands. Diseases affecting and destroying these glands, such as sebaceous adenitis or leishmaniosis, may present with scaling [3, 5]. Although very uncommonly, scaling in cats may also be greasy. This may occur due to excessive production of glandular secretions in primary seborrhea, a very rare disease in cats, and in the more common tail gland hyperplasia, also known as VetBooks.ir Scaling 151 Fig. 1 Scaling, erythema, and mild crusting on the pinna of a white cat with solar dermatitis Fig. 2 Scaling on the footpads of a cat affected by erythema multiforme stud tail (Fig. 3). Malassezia overgrowth may be related to sebaceous gland hyperplasia and abnormalities of the superficial lipid film, and consequently presents with greasy scaling [6, 7]. Follicular casting is uncommon in the feline species. It may be the clinical expression of follicular damage, as in demodicosis and dermatophytosis, or of destruction of the sebaceous glands in sebaceous adenitis [3]. A rare, recently reported congenital disease called sebaceous gland dysplasia occurs in kittens and is clinically characterized by generalized hypotrichosis, scaling and follicular casts [8]. Selected feline diseases presenting with scaling are listed in Table 1. VetBooks.ir 152 S. Colombo Fig. 3 Greasy seborrhea on the dorsal tail of a Persian cat with tail gland hyperplasia Diagnostic Approach Signalment and History Exfoliative diseases such as dermatophytosis (Fig. 4) or cheyletiellosis are commonly observed in kittens or in environmental conditions of crowding, such as breeding colonies or pet shops. Congenital diseases presenting with dry or greasy scaling and/or follicular casting are observed in kittens, although primary seborrhea and sebaceous gland dysplasia are extremely rare diseases [2, 9]. The most common cause of dry scaling in senior and geriatric cats is poor grooming, which may be due to obesity (Fig. 5) or concurrent systemic diseases such as chronic renal insufficiency, hyperthyroidism or diabetes mellitus. Less commonly, aged VetBooks.ir Scaling Table 1 Selected diseases presenting with dry or greasy scaling and follicular casts in cats 153 Poor grooming due to obesity or systemic disease Cheyletiellosis Demodicosis Dermatophytosis Malassezia overgrowth Leishmaniosis Adverse drug reaction Erythema multiforme Sebaceous gland dysplasia Primary seborrhea Sebaceous adenitis Plasma cell pododermatitis Solar dermatitis Tail gland hyperplasia Exfoliative dermatitis (thymoma-associated or not) Epitheliotropic cutaneous lymphoma Fig. 4 Scaling and erythema on the margin of the pinna of a kitten affected by dermatophytosis cats may be affected by neoplastic diseases or paraneoplastic syndromes [4, 9]. Dermatophytosis should always be considered in a Persian cat presenting with scaling and alopecia, regardless of age and lifestyle (Fig. 6). White cats and cats with white ears and/or muzzle are predisposed to solar dermatitis, if they are allowed outdoors and like laying in the sun. History in adult to older cats should always include concurrently or previously administered drugs which may cause adverse drug reactions. Finally, in a cat presenting with scaling, FIV and FeLV statuses should be evaluated. A FeLV- associated giant cell dermatosis has been reported to cause generalized, severe exfoliation, and both viral infections may predispose the cat to other infectious diseases [10]. VetBooks.ir 154 S. Colombo Fig. 5 Mild generalized scaling in a geriatric and obese cat Fig. 6 Focal alopecia and scaling in a Persian cat with dermatophytosis Clinical Presentation Dry scaling of variable severity is common in cats, and further clinical features should be considered to help listing the differential diagnoses. Generalized or dorsally distributed pityriasiform scaling in an older cat may be simply due to poor grooming, while in a recently acquired kitten, it may suggest cheyletiellosis, especially if pruritus is also reported. Exfoliative erythroderma, a clinical presentation characterized by scaling, erythema, and often alopecia, has been reported in senior or geriatric cats affected by epitheliotropic cutaneous lymphoma, although the disease is rare in the cat [4]. Exfoliative dermatoses in cats are often generalized, with a few exceptions. When scaling is associated to focal or multifocal alopecia, dermatophytosis is a possible diagnosis. Mild scaling and erythema on the pinnae of a white cat should prompt the clinician to include solar dermatitis in the differentials. VetBooks.ir Scaling 155 Fig. 7 Severe psoriasiform scaling in thymoma-associated exfoliative dermatitis Psoriasiform scaling is uncommon in cats. In middle-age to older cats, non- pruritic, severe, generalized, psoriasiform scaling with a history of starting on the head and neck and associated alopecia and erythema may be suggestive of thymoma or non-thymoma-associated exfoliative dermatitis (Fig. 7) [9, 11]. In thymoma- associated cases, coughing, dyspnea, depression, anorexia and weight loss are usually observed after the skin lesions. Psoriasiform scaling, follicular casting and alopecia with a generalized distribution, associated with deposition of darkcolored debris on the eyelids, may be consistent with sebaceous adenitis (Fig. 8), an extremely rare disease in the cat [3]. Scaling limited to the footpads may be a clinical feature of plasma cell pododermatitis (Fig. 9) [12]. Localized or generalized greasy scaling, erythema, pruritus and rancid smell may suggest Malassezia overgrowth (Fig. 10). This disease may be observed both in young, allergic cats and in older felines with severe systemic diseases, neoplasia or paraneoplastic syndromes [6, 7]. Greasy scaling on the dorsal aspect of the tail is the clinical presentation of tail gland hyperplasia, also known as stud tail. Diagnostic Algorithm This section is illustrated in Fig. 11. Red squares with numbers represent the steps of the diagnostic process, as explained below. 1 Perform skin scrapings and microscopic examination of scales and skin debris. The diagnostic approach to scaling in cats begins with simple tests to diagnose or rule out ectoparasites. Multiple skin scrapings should be performed to diagnose or rule out demodicosis, and fungal spores can also be seen surrounding and invading fragments of hair shafts in dermatophytosis. Cheyletiellosis may also be diagnosed with skin scrapings, although the most commonly used test is microscopic examination of acetate tape strips, after collecting scales VetBooks.ir 156 Fig. 8 Severe exfoliation and alopecia on the ventral trunk of a cat affected by sebaceous adenitis Fig. 9 Scaling on the footpads in a mild case of plasma cell pododermatitis S. Colombo VetBooks.ir Scaling 157 Fig. 10 Greasy, brown scaling in the interdigital spaces of an allergic Devon Rex cat with Malassezia overgrowth Scaling 1 Skin scraping Microscopic examination of scales and skin debris Demodicosis Cheyletiellosis Wood’s lamp examination Fungal culture Dermatophytosis Plasma cell pododermatitis Tail gland hyperplasia Obesity 3 Cytology 2 Malassezia overgrowth Signalment, History, Physical examination Poor grooming 6 4 Histopathology 5 Primary seborrhea Sebaceous gland dysplasia Solar dermatitis Sebaceous adenitis Erythema multiforme Adverse drug reactions Epitheliotropic cutaneous lymphoma Complete blood count Biochemistry Urinalysis FIV FeLV serology Leishmania serology Endocrinology testing X-ray Ultrasound TC/MRI (if appropriate) Go to chapter 9 Pruritus Diabetes mellitus Chronic kidney disease Hyperthyroidism Thymoma-associated exfoliative dermatitis Non thymoma-associated exfoliative dermatitis FeLV-associated giant cell dermatosis Leishmaniosis Fig. 11 Algorithm of the approach to feline scaling 2 directly from the cat’s coat or from material collected from the examination table after vigorous stroking of the coat. Perform Wood’s lamp examination and fungal culture. These two diagnostic tests, taken together, are diagnostic for dermatophytosis or, if negative results are obtained, are helpful to rule it out. Since dermatophytosis is common in cats, a fungal culture is appropriate in all cases presenting with scaling. 158 VetBooks.ir 3 4 5 6 S. Colombo Perform cytology. Cytology is particularly useful when greasy scaling is a presenting sign. Samples may be taken by impression smear, using a cotton swab or a piece of acetate tape to look for Malassezia yeasts. Since these yeasts may be identified in both young, allergic cats and older felines with systemic diseases, neoplasia or paraneoplastic syndromes, further investigations should always be carried out based on signalment, history and clinical examination. When a scaly footpad has to be sampled because plasma cell pododermatitis is suspected, fine needle capillary suction and aspiration are the preferred techniques. Consider the patient’s signalment, history and physical examination. In a young to adult cat presenting with greasy scaling on the dorsal tail, after ruling out ectoparasitic and fungal diseases, the diagnosis of tail gland hyperplasia is straightforward. When the patient is a senior or geriatric cat and presents with generalized dry scaling, poor grooming is a major differential. An aged cat may groom with difficulty because it is obese or because it suffers from a metabolic disease. Depending on other clinical signs, when identified on general physical examination, a variety of diagnostic tests may be appropriate. Perform blood testing, urinalysis and diagnostic imaging. In an older cat, basic information should always be obtained by taking a blood sample and a urine sample for complete blood count, biochemistry, urinalysis and serum total thyroxine (T4) concentrations. This will be useful also if sedation or general anesthesia is planned for biopsies. FIV and FeLV serology must be carried out if a cutaneous disease linked to one of these viruses is suspected, although this may become obvious only after histopathological examination. The same applies to serology for leishmaniosis, a rare disease in cats. Thoracic radiography and/or CT/MRI may be diagnostic for thymoma, which is often associated with exfoliative dermatitis. Take biopsies for histopathological examination. Histopathological examination usually confirms the diagnosis, whether the clinician is facing a congenital disease or an acquired one. Figure 11 summarizes the most important exfoliative disorders which require biopsies for the diagnosis. References 1. Paradis M, Scott DW. Hereditary primary seborrhea oleosa in Persian cats. Feline Pract. 1990;18:17–20. 2. Yager JA. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: a comparative review. Vet Dermatol. 2014;25:406–e64. 3. Noli C, Toma S. Case report three cases of immune-mediated adnexal skin disease treated with cyclosporin. Vet Dermatol. 2006;17(1):85–92. 4. Fontaine J, Heimann M, Day MJ. Cutaneous epitheliotropic T-cell lymphoma in the cat : a review of the literature and five new cases. Vet Dermatol. 2011;22(5):454–61. VetBooks.ir Scaling 159 5. Pennisi MG, Cardoso L, Baneth G, Bourdeau P, Koutinas A, Miró G, et al. LeishVet update and recommendations on feline leishmaniosis. Parasit Vectors. 2015;8:1–18. 6. Mauldin EA, Morris DO, Goldschmidt MH. Retrospective study: the presence of Malassezia in feline skin biopsies. A clinicopathological study. Vet Dermatol. 2002;13:7–14. 7. Ordeix L, Galeotti F, Scarampella F, Dedola C, Bardagi M, Romano E, Fondati A. Malassezia spp. overgrowth in allergic cats. Vet Dermatol. 2007;18:316–23. 8. Yager JA, Gross TL, Shearer D, Rothstein E, Power H, Sinke JD, Kraus H, Gram D, Cowper E, Foster A, Welle M. Abnormal sebaceous gland differentiation in 10 kittens (‘sebaceous gland dysplasia’) associated with generalized hypotrichosis and scaling. Vet Dermatol. 2012;23:136–e30. 9. Turek MM. Cutaneous paraneoplastic syndromes in dogs and cats : a review of the literature. Vet Dermatol. 2003;14:279–96. 10. Gross TL, Clark EG, Hargis AM, Head LL, Hainesh DM. Giant cell dermatosis in FeLV- positive cats. Vet Dermatol. 1993;4:117–22. 11. Brachelente C, vonTscharner C, Favrot C, Linek M, Silvia R, Wilhelm S, et al. Non thymoma- associated exfoliative dermatitis in 18 cats. Vet Dermatol. 2015;26:40–e13. 12. Dias Pereira P, Faustino AMR. Feline plasma cell pododermatitis: a study of 8 cases. Vet Dermatol. 2003;14:333–7. General References For definitions: Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 10 May 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin diseases of the dog and cat. Clinical and histopathologic diagnosis. 2nd ed. Oxford: Blackwell Publishing; 2005. Miller WH, Griffin CE, Campbell KL. Muller & Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Pruritus Silvia Colombo Abstract Pruritus, also called itching, is an irritating sensation in the upper surface of the skin, thought to result from stimulation of sensory nerve endings. Pruritus is common in cats and can be further classified based on its distribution (localized or generalized), location on the animal’s body and severity (mild, moderate, or severe). From a clinical point of view, pruritus in cats is most commonly caused by ectoparasitic, allergic, infectious or immune-mediated diseases. Cats manifest pruritus by overgrooming, which makes it particularly difficult to recognize and evaluate, and to be differentiated from pain or a behavioral problem. In a very young cat, ectoparasites and dermatophytosis are common, while in an adult cat, allergic and immune-mediated skin diseases should also be considered. History is relevant for concurrent drug administration or systemic disease and for severity and seasonality of pruritus. Most pruritic cats present with one (or more) of four clinical patterns, namely, head and neck pruritus, miliary dermatitis, self- induced alopecia and the eosinophilic granuloma complex. The diagnostic approach to pruritus should always be carefully followed in each of its steps in order to make a correct diagnosis. Definitions Pruritus, also called itching, is defined as an unpleasant feeling that causes the desire to scratch. In the vast majority of cases, the irritating sensation develops in the skin and is thought to result from stimulation of sensory nerve endings. In rare cases, pruritus may originate in the central nervous system. Pruritus is extremely common in veterinary dermatology and may be due to a wide variety of diseases. S. Colombo (*) Servizi Dermatologici Veterinari, Legnano, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_9 161 VetBooks.ir 162 S. Colombo It is an obvious clinical sign in dogs, while it can be very subtle in cats because it can be expressed as excessive grooming, which is a normal feline behavior, or because cats often hide from owners when they feel the desire to scratch. Pruritus is further classified based on its distribution (localized or generalized), location on the animal’s body and severity (mild, moderate, or severe). Pathogenesis The vast majority of the information about mechanisms, pathways, and mediators of pruritus comes from human or laboratory animal studies and has been reviewed elsewhere [1, 2]. From a clinical point of view, pruritus in cats is usually caused by ectoparasitic, allergic, infectious or immune-mediated diseases and can be worsened by concurrent factors such as stress, boredom, dry skin or high environmental temperature (Table 1). Although pruritus may be interpreted, in some cases, as a defense mechanism (scratching or licking to remove ectoparasites), skin lesions often occur as a consequence of behaviors carried out by the cat to relieve it. Cats manifest pruritus by overgrooming, in other words by increasing the frequency and intensity of a normal, programmed feline behavior. Cats groom to keep their skin and hair coat clean and healthy, to remove ectoparasites and dirt, to control their body temperature and to relieve tension or stress [3, 4]. Grooming in cats Table 1 Selected causes of pruritus in cats Pruritus Herpesvirus infection Superficial pyoderma Complicated chin acne Flea infestation Cheyletiellosis Notoedric mange Otodectic mange Demodicosis (Demodex gatoi) Trombiculiasis Dermatophytosis Malassezia overgrowth Flea-bite hypersensitivity Adverse reaction to food Feline atopic syndrome Mosquito-bite hypersensitivity Allergic/irritant contact dermatitis Adverse drug reaction Hyperthyroidism Pemphigus foliaceus Lymphocytic mural folliculitis Familial pedal eosinophilic dermatosis Urticaria pigmentosa-like dermatitis Idiopathic facial dermatitis of Persian and Himalayan cats VetBooks.ir Pruritus 163 include oral grooming, which is stroking the tongue through the pelage and nibbling with the incisor teeth, and scratch grooming, which is scratching with the hind paws [5]. According to one study, indoor, ectoparasite-free adult cats spend 50% of their time sleeping or resting. Of the time spent awake, oral grooming accounts for about 1 hour per day and scratch grooming for about 1 minute per day. Ninety-one percent of oral grooming is directed to multiple body regions, while scratch grooming is always directed to single regions [5]. Being the increased expression of a physiological behavior, overgrooming is often not recognized by the owner or not interpreted as a sign of pruritus, pain or stress. Moreover, cats tend to express their discomfort by hiding away from owners, who may not be aware of their pet’s overgrooming. For all these reasons, pruritus can be particularly difficult to recognize and evaluate in cats and to be differentiated from pain (e.g., licking the abdomen due to cystitis) or a behavioral problem (causing licking, scratching, or hair pulling). Idiopathic ulcerative dermatitis presents as a very severe and extremely pruritic, usually single, crusted ulceration affecting the dorsal neck (Fig. 1) in which pruritus, neuropathic itch and behavioral disorder have all been considered relevant in the disease pathogenesis. Idiopathic ulcerative dermatitis is diagnosed by exclusion of diseases which may induce pruritus to the dorsal neck, such as allergies and Fig. 1 Idiopathic/ behavioral ulcerative dermatitis on the dorsal neck VetBooks.ir 164 Table 2 Examples of non-dermatological diseases to be differentiated from pruritic skin diseases S. Colombo Feline idiopathic cystitis Psychogenic alopecia Feline idiopathic/behavioral ulcerative dermatitis Feline orofacial pain syndrome Feline hyperesthesia syndrome Localized neuropathies ectoparasites. A recent case report proposed that idiopathic ulcerative dermatitis may be a neuropathic itch syndrome, and the cat responded completely to topiramate, an anti-epileptic drug [6]. However, the same disease has also been investigated from a behavioral point of view. In 13 affected cats, in an open, uncontrolled study, environmental enrichment and improvement of overall welfare led to resolution of skin lesions, and psychotropic drugs were employed only in one case. The authors of this study proposed to change the disease name to feline behavioral ulcerative dermatitis [7]. Finally, an orofacial pain syndrome has been reported in cats. This syndrome occurs more commonly, although not exclusively, in Burmese cats and is clinically characterized by self-trauma to the face and oral cavity and occasionally by mutilation of the tongue. The disease may be associated with teeth eruption, dental disease, and stress and is suspected to be a neuropathic disorder, which should be considered in cats presenting with severe facial excoriations or ulcers [8]. In conclusion, overgrooming, which includes excessive licking and excessive scratching, may be the expression of non-dermatological diseases, which should always be considered when listing the differential diagnoses in an apparently “dermatological” case presenting for “pruritus” (Table 2). Diagnostic Approach Signalment and History Depending on the cat’s age, some diseases may be more likely than others. In a very young cat, ectoparasites and dermatophytosis are common, especially if the kitten has been found as a stray or adopted from a cattery, where crowding plays an important role too. Some diseases, such as dermatophytosis, cheyletiellosis and notoedric mange, are very contagious. These diseases may affect in contact animals as well as people, and questions about the presence of skin lesions on other pets or family members are mandatory. In an adult cat, allergic and immune-mediated skin diseases should also be considered, while in an older cat, hyperthyroidism may occur and explain the excessive grooming. Older cats may present with pruritus due to Malassezia overgrowth, which can be the marker of an underlying systemic disease or paraneoplastic syndrome (Fig. 2) [9]. VetBooks.ir Pruritus 165 Fig. 2 Alopecia and brown greasy material typical of Malassezia overgrowth in an old cat with pancreatic paraneoplastic alopecia Fig. 3 Alopecia and excoriations on the head and pinnae of a cat affected by seasonal feline atopic syndrome History should include drugs administered for other diseases, which may cause adverse drug reactions, and ectoparasite prevention. Immunosuppressive therapy or systemic disease may predispose the cat to dermatophytosis if it gets exposed, for example, because the owner adopts a new kitten. Seasonality of pruritus may be useful to limit the list of differentials: ectoparasites and seasonal feline atopic syndrome are more likely in a cat scratching in spring and summer (Fig. 3). Severity of pruritus should also be analyzed in depth because some diseases are characterized by extremely severe pruritus (notoedric mange) while in others pruritus may be very mild (cheyletiellosis, dermatophytosis). Persian cats of any age are predisposed to dermatophytosis. An older Persian cat may be affected by dermatophytosis, if it is an asymptomatic carrier, without the need for contact with a diseased animal [10]. 166 S. Colombo VetBooks.ir Clinical Presentation In cats, pruritus is expressed by overgrooming; however, only increased scratching is easily recognized by the owner. Since they scratch with their hind paws, excoriations usually involve areas that the cat can reach, such as the face, ears, head and neck. The so called “head and neck pruritus” is a common clinical presentation in pruritic cats (Fig. 4) [11]. Variably sized excoriations, erosions and ulcers in these locations may be very severe and deep and are often secondarily infected. This clinical presentation is specifically addressed in Chapter, Excoriations, Erosions and Ulcers. Less obviously, alopecia may be caused by an overgrooming, pruritic cat [11]. Self-induced alopecia is characterized by the presence of very short hair fragments which can be observed by looking closely at the skin or with the help of a magnifying lens. Hair cannot be easily epilated. The alopecic area usually has very well- defined margins, with abrupt change to normal hair, and involves parts of the body that can be reached by the tongue (Fig. 5). Self-induced alopecia is described in Chapter, Alopecia. Miliary dermatitis is a peculiar feline clinical presentation also associated with pruritus [11]. It is characterized by small, crusted papules “resembling millet seeds,” hence the name, which are more easily felt by touching through the haircoat than Fig. 4 Excoriations on the head of an allergic cat VetBooks.ir Pruritus 167 Fig. 5 Self-induced alopecia on the abdomen of a cat with flea-bite hypersensitivity Fig. 6 Small, crusted papules typical of miliary dermatitis seen (Fig. 6). Miliary dermatitis is often associated with self-induced alopecia and is addressed in Chapter, Papules, Pustules, Furuncles and Crusts. Another clinical pattern associated with pruritus is a group of lesions named eosinophilic granuloma complex or eosinophilic dermatitides (Figs. 7 and 8) [12]. These conditions, or clinical presentations, are often caused by allergic diseases and are discussed in Chapter, Plaques, Nodules and Eosinophilic Granuloma Complex Lesions. Many pruritic diseases, in cats, can be associated with one or more of the four previously described clinical patterns and/or with recurrent otitis (Chapter, Otitis). However, each disease has its own preferential distribution of pruritus and lesions on the animal body (Table 3). Some other unusual presentations are also associated with pruritus and may be caused by hypersensitivity reactions to food or environmental allergens, at least in some cases. Lymphocytic mural folliculitis, for example, is a histopathological reaction pattern occasionally identified in allergic cats 168 S. Colombo VetBooks.ir Fig. 7 Eosinophilic plaques on the abdomen Fig. 8 Bilateral indolent ulcer in a domestic short-haired cat presenting with pruritus, localized or generalized, partial or complete alopecia and scaling (Fig. 9) [13]. Urticaria pigmentosa-like dermatitis occurs in Devon Rex or Sphynx cats and is clinically characterized by an erythematous to hyperpigmented papular eruption, which is often pruritic (Fig. 10) [14, 15]. Pruritic and non-pruritic dermatoses may be secondarily infected by bacteria or yeasts. Although this occurs in cats much less frequently than in dogs, one should always keep into consideration and diagnose/rule out these diseases when examining a pruritic cat [9, 16]. Diagnostic Algorithm This section is illustrated in Fig. 11. Red squares with numbers represent the steps of the diagnostic process, as explained below. Pruritus 169 VetBooks.ir Table 3 Common locations of selected feline skin diseases associated with pruritus Locations Face Chin Rump Thorax, abdomen Dorsum Ear canal Pinnae, paws, abdomen Pinnae, face, neck, paws, perineum Head, pinnae, paws, tail, generalized Chin, claw folds, face, ear canal, generalized Rump Dorsal nose, pinnae, paws Abdomen, medial thighs, head, neck Head, pinnae, claw folds, abdomen Paws Face Fig. 9 Alopecia, scaling and hyperpigmentation on the head of a cat with lymphocytic mural folliculitis Disease Herpesvirus infection Complicated chin acne Flea infestation Demodicosis (Demodex gatoi) Cheyletiellosis Otodectic mange Trombiculiasis Notoedric mange Dermatophytosis Malassezia overgrowth Flea-bite hypersensitivity Mosquito-bite hypersensitivity Other allergic diseases Pemphigus foliaceus Familial pedal eosinophilic dermatosis Idiopathic facial dermatitis of Persian and Himalayan cats VetBooks.ir 170 S. Colombo Fig. 10 Coalescing, crusted, and non-crusted papules in a Sphynx cat with urticaria pigmentosa- like dermatitis Pruritus Flea infestation Demodicosis Notoedric mange Otodectic mange Cheyletiellosis Trombiculiasis Skin scraping Microscopic examination of hair shafts, skin debris 1 and/or ear cerumen Wood’s lamp examination 2 Fungal culture Dermatophytosis Self-induced alopecia Malassezia overgrowth Superficial pyoderma Complicated chin acne 4 Dentistry examination Cytology Histopathology Eosinophilic inflammation Head and neck pruritus Miliary dermatitis Orofacial pain syndrome Histopathology 2a 3 Eosinophilic granuloma complex 4 Mosquito-bite hypersensitivity Familial pedal eosinophilic dermatosis Urticaria pigmentosa-like dermatitis Urinalysis Bacterial culture and sensitivity testing Ultrasound Complete blood count Biochemistry Endocrinology testing 4 Feline idiopathic cystitis Hyperthyroidism Therapeutic trial for fleas Herpesvirus infection Idiopathic facial dermatitis of Persian and Himalayan cats Pemphigus foliaceus Adverse drug reaction Lymphocytic mural folliculitis Psychogenic alopecia Idiopathic/behavioral ulcerative dermatitis Flea-bite hypersensitivity Behavioral examination Fig. 11 Diagnostic algorithm of pruritus 6 7 5 Elimination diet Adverse reaction to food Feline atopic syndrome 7 Neurologic examination Feline hyperesthesia syndrome Localized neuropathies Pruritus VetBooks.ir 1 171 Perform skin scrapings and microscopic examination of hair, skin debris and/or ear cerumen. In the diagnostic approach to pruritus, it is mandatory to begin with simple tests to diagnose or rule out ectoparasites. Multiple skin scrapings are useful for notoedric mange and demodicosis, and fungal spores can be seen surrounding and invading fragments of hair shafts in dermatophytosis. Cheyletiellosis and trombiculiasis may be diagnosed by microscopic examination of acetate tape strips, after collecting samples directly from the cat’s coat or, for Cheyletiella spp., from the material collected from the examination table after vigorous stroking of the coat. This latter way of collecting specimens may also be used to find flea dirt, together with coat combing. If pruritus is mainly affecting the ears, microscopic examination of ear cerumen is required to diagnose otodectic mange. 2 Perform Wood’s lamp examination and fungal culture. The second step is to rule out or diagnose dermatophytosis, which may have already been suspected after microscopic examination of hair shafts. Wood’s lamp examination may support the diagnostic hypothesis and fungal culture is required to confirm dermatophytosis. If negative results are obtained, these tests are helpful to rule it out. Since dermatophytosis is common in cats, a fungal culture is appropriate in all cases, although pruritus can be of variable severity. 2a If the clinical presentation is self-induced alopecia involving the groin and abdomen, urinalysis, bacterial culture and sensitivity testing, and abdominal ultrasound should be performed to investigate feline idiopathic cystitis or other urinary tract diseases. Self-induced alopecia in an old cat may also be caused by hyperthyroidism, and hematology, biochemistry and endocrine testing should be carried out in this specific situation. 3 Perform cytology. Cytology is the easiest and quickest diagnostic test to support the clinical suspicion of diseases characterized by eosinophilic inflammation, which are numerous and very common in cats. Eosinophilic plaque and granuloma and miliary dermatitis are often clinical patterns of allergy, characterized by eosinophilic inflammation, and the diagnostic process should continue to identify the primary disease. On the other hand, familial pedal eosinophilic dermatosis, mosquito-bite hypersensitivity and urticaria pigmentosa-like dermatitis show eosinophilic inflammation on cytology and are specific diseases which should be confirmed by histopathological examination. Cytology is also important because secondary bacterial or yeast infections may complicate the primary disease and increase the severity of pruritus, although this occurs less frequently in cats compared to dogs. Samples may be taken by impression smear, using a cotton swab or a piece of acetate tape to look for Malassezia yeasts, bacteria and inflammatory cells. Finally, identification of acantholytic cells admixed with neutrophils may suggest pemphigus foliaceus. 172 VetBooks.ir 4 5 6 7 S. Colombo Perform histopathology. As anticipated, histopathology is the confirmatory diagnostic test for many feline diseases cytologically characterized by eosinophilic inflammation. When pruritus affects mainly the face, histopathological examination is required to diagnose idiopathic facial dermatitis of Persian and Himalayan cats and herpesvirus infection, although in this latter disease immunohistochemistry may be necessary to confirm the etiology. In cases with clinical manifestation of severe self-trauma to the face and oral cavity, a dental examination may be required to investigate orofacial pain syndrome. Histopathological examination is useful to diagnose pemphigus foliaceus and, together with history, adverse drug reactions. Perform a therapeutic trial for fleas. In the majority of cases presenting for pruritus, ectoparasites and dermatophytosis can be ruled out at the beginning of the diagnostic approach, and cytological examination only shows secondary infections or eosinophilic inflammation, which is neither specific nor particularly useful. These cases usually present with one of the four clinical patterns typical of pruritus and should be investigated in a systematic way. The first step is a therapeutic trial for fleas, which may have not been identified during the initial investigations for ectoparasites. A positive response to the trial suggests flea-bite hypersensitivity. Perform an elimination diet. If the therapeutic trial for fleas is unsuccessful, the second step is performing an elimination diet with novel protein sources or a hydrolyzed diet, to be carried out for at least 8 weeks. If the cat improves on the diet, challenge with the previous food is required to diagnose an adverse reaction to food. After ruling out food as the cause of pruritus, the clinician is left with a possible diagnosis of feline atopic syndrome. There are different treatment options for environmental allergy in cats and the diagnosis is confirmed by response to treatment. Depending on history and clinical presentation, in some cases, a behavioral problem can be suspected, especially if the cat presents with self-induced alopecia or ulcerative dermatitis affecting the dorsal neck. In other cases, a neurologic problem such as feline hyperesthesia syndrome may be considered and needs to be investigated. These conditions are usually addressed only when all the other differentials have been ruled out, and the cat does not respond to treatment for feline atopic syndrome. References 1. Metz M, Grundmann S, Stander S. Pruritus: an overview of current concepts. Vet Dermatol. 2011;22:121–31. 2. Gnirs K, Prelaud P. Cutaneous manifestations of neurological diseases: review of neuro- pathophysiology and diseases causing pruritus. Vet Dermatol. 2005;16:137–46. 3. Beaver BV. Feline behavior. A guide for veterinarians. Second edition. St. Louis: WB Saunders; 2003. VetBooks.ir Pruritus 173 4. Bowen J, Heath S. Behaviour problems in small animals. Practical advice for the veterinary team. Philadelphia: Elsevier Saunders; 2005. 5. Eckstein RA, Hart BL. The organization and control of grooming in cats. Appl Anim Behav Sci. 2000;68:131–40. 6. Grant D, Rusbridge C. Topiramate in the management of feline idiopathic ulcerative dermatitis in a two-year-old cat. Vet Dermatol. 2014;25:226–e60. 7. Titeux E, Gilbert C, Briand A, Cochet-Faivre N. From feline idiopathic ulcerative dermatitis to feline behavioral ulcerative dermatitis: grooming repetitive behavior indicators of poor welfare in cats. Front Vet Sci. 2018; https://doi.org/10.3389/fvets.2018.00081. 8. Rusbridge C, Heath S, Gunn-Moore D, Knowler SP, Johnston N, McFadyen AK. Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases. J Feline Med Surg. 2010;12:498–508. 9. Mauldin EA, Morris DO, Goldschmidt MH. Retrospective study: the presence of Malassezia in feline skin biopsies. A clinicopathological study. Vet Dermatol. 2002;13:7–14. 10. Moriello KA, Coyner K, Paterson S, Mignon B. Diagnosis and treatment of dermatophytosis in dogs and cats.: clinical consensus guidelines of the world Association for Veterinary Dermatology. Vet Dermatol. 2017;28(3):266–8. 11. Hobi S, Linek M, Marignac G, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 12. Buckley L, Nuttall T. Feline eosinophilic granuloma complex(ITIES): some clinical clarification. J Feline Med Surg. 2012;14:471–81. 13. Rosenberg AS, Scott DW, Erb HN, McDonough SP. Infiltrative lymphocytic mural folliculitis: a histopathological reaction pattern in skin-biopsy specimens from cats with allergic skin disease. J Feline Med Surg. 2010;12:80–5. 14. Noli C, Colombo S, Abramo F, Scarampella F. Papular eosinophilic/mastocytic dermatitis (feline urticaria pigmentosa) in Devon rex cats: a distinct disease entity or a histopathological reaction pattern? Vet Dermatol. 2004;15:253–9. 15. Ngo J, Morren MA, Bodemer C, Heimann M, Fontaine J. Feline maculopapular cutaneous mastocytosis: a retrospective study of 13 cases and proposal for a new classification. J Feline Med Surg. https://doi.org/10.1177/1098612X18776141. 16. Yu HW, Vogelnest L. Feline superficial pyoderma: a retrospective study of 52 cases (2001- 2011). Vet Dermatol. 2012;23:448–e86. General References For definitions: Merriam-Webster Medical Dictionary. http://merriam-webster.com Accessed 10 May 2018. Albanese F. Canine and feline skin cytology. Cham: Springer International Publishing; 2017. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: The McGraw-Hill Companies; 2012. Miller WH, Griffin CE, Muller CKL. Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier; 2013. Noli C, Toma S. Dermatologia del cane e del gatto. 2nd ed. Vermezzo: Poletto Editore; 2011. VetBooks.ir Otitis Tim Nuttall Abstract Otitis externa and media are common in cats, although almost all infections are secondary. The underlying conditions must be diagnosed and managed for resolution. The approach to feline otitis is different from that in dogs. There are important differences in the ear anatomy of dogs and cats, although there is less breed variation among cats. The role of primary, secondary, predisposing and perpetuating (PSPP) factors is less clear in feline otitis, with fewer predisposing and perpetuating problems. The primary aetiology of otitis is different from dogs with less of a role for hypersensitivity dermatoses. There are a variety of cat-specific conditions, including inflammatory polyps, cystoadenomatosis, and proliferative and necrotising otitis. This chapter will describe the anatomy and physiology of feline ears, how to use clinical examination, cytology, culture and imaging in diagnosis, ear cleaning, treatment of otitis externa and otitis media, and the diagnosis and management of specific ear conditions in cats. Introduction Feline otitis requires a different approach to diagnosis and treatment compared to canine otitis. The aetiology is different and many conditions are specific to cats. Otitis is less common and less well associated with common skin diseases in cats than in dogs. For example, otitis has been reported in 16% [1] to 20% [2] of cats with hypersensitivity dermatitis. In contrast, up to 80% of dogs with atopic dermatitis may suffer from recurrent otitis externa [3]. In addition, the PSPP (primary, secondary, predisposing and perpetuating) approach is less useful in cats compared T. Nuttall (*) Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, UK e-mail: tim.nuttall@ed.ac.uk © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_10 175 VetBooks.ir 176 T. Nuttall to dogs. While it is true that ear infections are invariably secondary and that there are a number of defined primary causes of otitis in cats, the role of predisposing factors and perpetuating problems in initiating otitis and the progression to chronic disease is less clear. Finally, cats can be more sensitive to ototoxicity than dogs, and topical treatments and ear cleaners must be selected and used with care. It is very important to recognise that cats with recurrent ear infections have an underlying problem – they do not have an antimicrobial deficiency! Overuse of antimicrobials can mask the primary condition (which can get more severe and difficult to manage) and select for antimicrobial resistance (which can complicate future treatment). Successful management requires diagnosis and appropriate treatment of the primary cause. Anatomy and Physiology Feline ear canal anatomy is similar to that in dogs, although with much less variation among breeds and individuals [4, 5] (Chapter, Structure and Function of the Skin). The Pinnae With the exception of some breeds such as the Scottish Fold, cats have an upright pinna. The skin of the pinnae and ear canals is continuous with the skin over the rest of the body. The dorsal surface is covered with densely haired skin that is loosely attached to the underlying cartilage. The skin on the ventral surface is tightly attached to the cartilage. Hairs arising on the rostral margin of the pinna fold back across the pinnal surface and ear canal opening and probably limit entry of foreign material (Fig. 1). Touching these hairs can elicit ear flicking or head shaking. They can be extensive in long-haired breeds. The ventral surface of the pinna is otherwise hairless. There is a complex array of cartilage folds at the base of the pinna. The most important to recognise is the tragus (Fig. 1), which forms the lateral margin of the vertical canal. The opening to the vertical ear canal is located behind the tragus. Ear Canals and Cerumen The skin of the ear canals is continuous with that of the ventral pinna. It is thin, hairless and tightly opposed to the underlying ear canal cartilages. The auricular cartilage is continuous with the pinna and forms the vertical ear canal (Fig. 2). It is loosely embedded within connective tissue and is reasonably mobile. The auricular cartilage is connected to the annular cartilage by fibrous tissue, which gives some flexibility and mobility. The junction is visible as a dorsal ridge extending into the ear canal lumen (Fig. 3). The annular cartilage forms the short horizontal ear canal VetBooks.ir Otitis 177 Fig. 1 The inner surface of the pinna (rostral is to the bottom left; caudal to the upper right). Blue arrow – hairs arising from the rostral pinna margin and extending caudally across the pinna; black arrow – the tragus and is connected to the bony external auditory meatus by fibrous tissue. This gives some flexibility but the horizontal ear canal is much less mobile than the vertical ear canal and pinna. The horizontal ear canal is typically 6–9 mm in diameter, which can limit access of otoscope cones. Cerumen is typically sparse in healthy cat ears and has a film-like creamy consistency compared to dogs. Outward, lateral migration of the stratum corneum moves the cerumen, desquamated cells and debris to the opening of the ear canals. Here, the cerumen dries, detaches and is removed through normal grooming. Tympanic Membrane The tympanic membrane (Fig. 4) separates the external ear canals from the middle ear. It is housed within the bony external auditory meatus (Fig. 2) facing horizontally at an angle from dorso-lateral to ventro-medial, although it can be near vertical in some cats. The dorsal pars flaccida is narrow and much less prominent than in VetBooks.ir 178 T. Nuttall Auricular cartilage Annular cartilage Auditory ossicles External auditory meatus Semicircular ducts Opening of the Eustachian tube Cochlea Dorsolateral compartment Tympanic membrane Bulla External ear canal Promontory Opening between bulla compartments Septum Ventromedial compartment of tympanic cavity Fig. 2 Schematic diagram of the external ear canals, middle ear and inner ear Fig. 3 View of the base of the vertical ear canal. The arrow indicates the ridge or shelf formed at the junction of the vertical and horizontal ear canals dogs. The pars tensa forms a thin, grey-white, translucent membrane with prominent striations radiating from the manubrium of the malleus. The malleus forms a white straight or slightly curved structure running ventrally from the rostro-dorsal edge of the tympanic membrane. The concavity of the curve faces rostrally, but this is less marked than in dogs. The malleus is surrounded by a ring of blood vessels. VetBooks.ir Otitis 179 Fig. 4 Normal tympanic membrane in a healthy cat. A – attachment of the malleus; B – pars flaccida; C – pars tensa Middle Ear The middle ear (Fig. 2) is divided by a bony shelf into ventro-medial (pars endotympanica) and dorso-lateral (pars tympanica) compartments. The dorso-lateral compartment is bounded laterally by the tympanic membrane, dorsally by the epitympanic recess and medially by the lateral wall of the cochlea. The epitympanic recess contains the auditory ossicles and openings to the cochlear (auditory window) and vestibular systems (vestibular window). The Eustachian tube opens in the medial wall of the middle ear near the origin of the bony shelf and connects the middle ear with the pharynx. A sympathetic nerve trunk runs close to the opening of the Eustachian tube. It is quite superficial in cats and vulnerable when removing polyps, flushing the middle ear and/ or treating otitis (which can result in Horner’s syndrome). The middle ear is lined with a mucous epithelium continuous with that of the Eustachian tube and pharynx. The Eustachian tube allows air pressure to equalise across the tympanic membrane and mucus from the middle ear to drain into the pharynx. A small opening in the bony shelf allows mucus from the ventral bulla compartment to drain through the Eustachian tube. General Approach to Otitis 1. Identify and treat the infection. • Use ear cytology to identify Malassezia, bacteria and inflammatory cells. • When necessary, perform culture to identify the microorganisms and their antimicrobial susceptibility. VetBooks.ir 180 T. Nuttall 2. Identify and manage the primary cause. • Perform a thorough history and full clinical examination. • Examine the ear canals for clinical lesions, type of discharge, mites, foreign bodies, inflammatory polyps and tumours. • Examine the tympanic membrane for signs of rupture and otitis media. 3. Identify and manage any predisposing and perpetuating causes. • Clinically assess the extent and severity of chronic inflammatory changes. • Consider radiographs, CT scans or MRI scans. Diagnostic Procedures Examining the Ear The ears should be carefully examined for any abnormalities. Certain clinical signs are often highly specific for primary conditions in feline otitis (see below). Healthy ears should be freely mobile, pliable, non-painful and non-pruritic and have little to no discharge. Very firm, immobile ear canals are often irreversibly fibrosed and/or mineralised. The skin should be pale, thin and smooth. The ear canals should be open with a thin, smooth and pale lining, little to no discharge and a normal tympanic membrane. However, the narrow diameter of cats’ ear canals can make otoscopic examination of the horizontal ear canal difficult. The tympanic membrane may not be easily visible in diseased ears. This should not preclude treatment, although the possibility of a ruptured membrane should be considered. Full examination may therefore need sedation, anaesthesia, removal of any discharge and/or treatment to open the ear canal lumen. Despite this, careful examination in a conscious cat can help identify the cause of the otitis as well as the extent and severity of secondary changes without otoscopic examination. The nature of the discharge can indicate the likely problem and/or infection, but the appearance of the dried discharge at the opening of the ears can be misleading and fresh material from the ear canals should be evaluated. Cytology Cytology is mandatory in all cases of otitis where it can identify the most likely organisms. This is particularly useful in mixed infections, where culture may identify several organisms with different susceptibility patterns. Samples should be collected from the ear canal with swabs or curettes. Mites can be found in material collected in mineral oil under x40 magnification. Air-dried or heat-fixed material stained with a modified Wright–Giemsa stain can be examined under high magnification (x400 or x1000 oil immersion) to see cells and microorganisms. It is important to recognise biofilms, which form thick, dark and slimy exudates. They appear as variably thick veil-like material (Fig. 5a, b) on cytology that may VetBooks.ir Otitis 181 obscure bacteria and cells. Biofilms are becoming increasingly common in otitis. Many microorganisms can produce biofilms, which facilitate adherence to the ear canal epidermis, middle ear lining and surrounding hairs. They also inhibit antimicrobials by providing physical protection and by altering metabolic activity. The net result is that much higher antimicrobial concentrations predicted by in vitro testing are required – in effect the minimum inhibitory concentration (MIC) is increased. Specific anti-biofilm measures (see below) should be used in all cases where they are present. The numbers of yeast, cocci, rods, neutrophils and epithelial cells should be quantified. Staphylococci (Fig. 5b) and Malassezia spp. (Fig. 6) are straightforward to identify, and a good estimate of their probable sensitivity can be made based on knowledge of local resistance patterns and previous treatment. Gram-negative bacteria (Fig. 7), however, are harder to differentiate on cytology alone. Fig. 5 (a) The typical dark, thick and slimy appearance of biofilm from the ear canals; (b) – a biofilm-associated staphylococcal infection showing coccoid bacteria embedded in a veil-like matrix (Rapi-Diff II® stain; ×400 magnification). Staphylococci typically form pairs, groups of 4 and irregular clumps a b VetBooks.ir 182 T. Nuttall Fig. 6 Malassezia otitis with large numbers of budding yeasts (Rapi-Diff II® stain; ×400 magnification) Fig. 7 Pseudomonas otitis with large numbers of rod bacteria (A) and neutrophils (B) embedded in a slimy matrix (C) consistent with a biofilm. All bacteria that stain with modified Wright–Giemsa stains will stain dark blue – their Gram-negative identity can only be inferred (Rapi-Diff II® stain; ×400 magnification) Bacterial Culture and Antimicrobial Susceptibility Testing Bacterial culture and susceptibility testing is not necessary in most cases of otitis externa if topical therapy is used, as the antibiotic concentration in these products greatly exceeds the minimum inhibitory concentration (MIC) for the bacteria. Great care must be taken in interpreting antibiotic susceptibility and resistance results because the susceptibility–resistance breakpoints are based on tissue concentrations after systemic treatment. This does not necessarily mean that the bacteria are resistant to the antimicrobial because sufficiently high antibiotic levels, as achieved with topical therapy, may still exceed the MIC. Sensitivity data are therefore very poorly predictive of the response to topical drugs because concentrations in the ear canal are much higher. The response to treatment is best assessed using clinical signs and cytology. VetBooks.ir Otitis 183 Bacterial cultures can help identify the bacteria involved in the infection. This can be useful for less common organisms that are hard to differentiate on cytology and/or where the antimicrobial susceptibility patterns are less predictable. Antibiotic sensitivity data should be used to predict the efficacy of systemic drugs in case these are used (e.g. in case of otitis media), although the concentration in the ear tissues may be low and high doses are needed. In addition, biofilms that inhibit antimicrobial penetration and efficacy effectively increase the in vivo MIC, meaning that in vitro tests over-estimate antimicrobial susceptibility. Diagnostic Imaging Diagnostic imaging techniques include radiography, CT and MRI. Radiography (Fig. 8) is the most widely available but is the least sensitive. A full series should include dorso-ventral, lateral, right and left lateral oblique, and, where necessary, rostro-caudal open mouth views [6]. CT scans (Fig. 9) are less widely available, but are fast, can be done under sedation, and are highly accurate for bony and softtissue changes. Post-contrast evaluation of bone- and soft-tissue weighted views can reveal the extent and severity of inflammation as well differentiate tissue density Fig. 8 Rostro-caudal open mouth radiograph of a cat with unilateral otitis media. The left middle ear compartments have a normal dark air-filled appearance. The right middle ear is filled with opaque material consistent with soft-tissue or fluid T. Nuttall VetBooks.ir 184 Fig. 9 CT scan of a cat with bilateral otitis media. There is some thickening of the tympanic bulla wall consistent with chronic inflammation (compare to the bulla walls in Fig. 8). The ventral compartments are filled with soft tissue, which density analysis revealed to be fluid. The right dorsal compartment is also filled with soft tissue that was shown to be solid. The cat had an inflammatory polyp in the right ear and mucoid congestion in the ventral bullae in both ears (e.g. solid tissue, fat and fluid). MRI is best for evaluating the soft tissues and nerves around the ears, but will not image bony structures adequately. Ear Cleaning and Ear Flushing Ear cleaning removes debris and microbes from the canal [4, 5, 7]. Some ear cleaners have broad-spectrum antimicrobial activity [8]. Very waxy or exudative ears should be cleaned daily during treatment, but this isn’t necessary if there is less debris. It is important to demonstrate effective ear-cleaning techniques to owners. Ear Cleaners Ceruminolytic (lift debris off the epidermis) and ceruminosolvent (soften cerumen) cleaners (i.e. propylene glycol, lanolin, glycerine, squalane, butylated hydroxytoluene, cocamidopropyl betaine and mineral oils) are useful for softening and removing dry waxy debris and/or wax plugs. Surfactant-based ear cleaners (i.e. docusate sodium, calcium sulfosuccinate and similar detergents) are better in more seborrhoeic ears and purulent ears. Tris-EDTA has very little ceruminolytic or detergent activity, but is soothing in ulcerated purulent ears and is safer if the tympanic VetBooks.ir Otitis 185 membrane is ruptured. Astringents (i.e. isopropyl alcohol, boric acid, benzoic acid, salicylic acid, sulphur, aluminium acetate, acetic acid and silicon dioxide) can help prevent maceration of the epithelial lining of the canal. Antimicrobials (e.g. p-chlorometaxylenol [PCMX], chlorhexidine and ketoconazole) can help treat and prevent infections. Tris-EDTA has little antimicrobial activity by itself, but high concentrations can potentiate the effect of antibiotics and chlorhexidine [9, 10]. Ear cleaners should be used with some caution in cats, and some ingredients (e.g. detergents, acids and alcohols) can irritate the ears and/or trigger ototoxicity. Ear Flushing Thorough ear flushing under general anaesthetic is the only way to clean the deeper ear canal and middle ear [4, 5, 7]. A tomcat catheter, urinary catheter or feeding tube can be inserted into the ear canals and, if necessary, middle ear under direct visualisation through an operating head or, preferably, video otoscope. The longer length, narrower diameter, magnification and visual clarity of a video otoscope make the procedure much easier, more accurate and safer. Ear flushing should be done with saline or water to minimise the risk of ototoxicity or Horner’s syndrome. This is flushed and aspirated into the ear canals and/or middle ear until clean. It may be necessary to use a ceruminolytic initially to help soften and loosen stubborn debris, but this should be carefully and thoroughly flushed out afterwards. Myringotomy A myringotomy (deliberate rupture of the tympanic membrane) should be considered if the ear drum is intact but there is evidence of middle ear disease (e.g. clinical signs, abnormal tympanic membrane and/or diagnostic imaging findings) [4, 5, 7]. A catheter, stylet, spinal needle or curette can be used to puncture the ventro-lateral portion of the tympanic membrane (Fig. 4). This avoids the important structures in the epitympanic recess. It’s only possible to get access to the dorso-lateral tympanic bulla through the tympanic membrane as the bony shelf (while allowing some communication) prevents direct entry into the ventro-medial compartment. Diseases of the Pinna Diseases of the pinna (Table 1) are relatively common in cats. They are normally associated with more generalised skin conditions that are covered in detail elsewhere in this book. In contrast to the more specific causes of otitis, these conditions rarely affect the ear canals. 186 T. Nuttall VetBooks.ir Table 1 Diseases of the pinna Alopecia Pruritic and eosinophilic dermatitis Pustules and crusting Necrosis and ulceration Thickening, scaling and pigmentation (with or without distortion) Nodules and ulcers Nodules, ulcers and sinus tracts Hyperadrenocorticism Hypothyroidism (very rare) Dermatophytosis Demodex spp. (rare) Follicular dysplasia (Devon rex cats) Lymphocytic and other mural folliculitis Alopecia mucinosa Mosquito-bite hypersensitivity Other biting insects (including rabbit fleas) Head and neck dermatitis Eosinophilic granuloma complex Notoedres cati and Sarcoptes scabiei (rare) Pemphigus foliaceus Drug reactions Vasculitis Cold agglutinin disease Frostbite Actinic keratosis Cutaneous horn Multicentric squamous cell carcinoma in situ (Bowen’s disease) Auricular chondritis Squamous cell carcinoma Cat bite abscess or cellulitis Aural haematoma (rare) Cryptococcus spp. and other deep fungal infections Deep bacterial infections (e.g. Actinomyces and Nocardia spp.) Mycobacterial infections Otitis Externa Clinical Signs Clinical signs of otitis externa include pruritus, head shaking, inflammation and discharge. The division into erythroceruminous and suppurative otitis is less clear than in dogs. Waxy ceruminous to seborrheic discharges may be sterile or involve Malassezia or (less commonly) a bacterial overgrowth (i.e. there are no neutrophils or other inflammatory exudates). Purulent otitis is relatively more common than in dogs (where erythroceruminous otitis predominates). However, severe ulcerative Pseudomonas otitis is uncommon in cats. Acute, unilateral otitis externa can be seen with foreign bodies, whereas chronic unilateral otitis suggests neoplasia or an inflammatory polyp. Bilateral otitis externa in cats is most commonly associated with otodectic mange, but chronic cases can be associated with adverse food reactions or other hypersensitivity diseases. Otitis 187 VetBooks.ir Table 2 Primary, predisposing and perpetuating factors in otitis externa Primary (the actual cause of the ear disease) Predisposing (make otitis more likely or more likely to be severe) Perpetuating (prevent resolution) Otodectes cynotis Demodex spp. (rare) Foreign bodies (rare) Adverse food reactions Feline atopic syndrome (feline atopic dermatitis) Inflammatory polyps Cystoadenomatosis Proliferative and necrotising otitis Ceruminous gland neoplasia Seborrheic otitis Conformation (e.g. pendulous, hairy, narrow ears and ceruminous ears; rare in cats) Swimming (very rare in cats) Maceration or irritation of canal epithelium with cleaning or medication Chronic pathological changes (e.g. decreased epithelial migration, sebaceous and ceruminous hyperplasia, increased discharge, oedema, fibrosis, thickening and stenosis, and calcification) Otitis media The PSPP Approach Ear infections are almost always secondary to primary, predisposing and perpetuating factors (the PSPP approach – Table 2) [4, 5]. The primary cause of the otitis must be diagnosed and treated. Predisposing factors may not be easily countered or managed, but should alert clinicians to animals that will be more likely than others to have recurrent otitis. However, with the exception of excessive cleaning or medication, these are less important in cats compared to dogs. Failure to address all the perpetuating causes of otitis externa commonly results in relapsing chronic otitis. Perpetuating causes can change over the course of chronic otitis and will eventually lead to irreversible changes that require a total ear canal ablation. Bacterial and Malassezia Infections Staphylococcal bacteria (e.g. Staphylococcus pseudintermedius and S. felis) are most common, but other organisms can include streptococci, Pasteurella multocida, E. coli, Klebsiella pneumoniae, and/or Proteus, Pseudomonas, Corynebacteria and Actinomyces spp. [4, 5]. Mixed bacterial infections are frequently seen. Many staphylococci and Gram-negative strains can produce biofilms [11]. These inhibit cleaning, prevent penetration and activity of antimicrobials (effectively increasing the MIC) and provide a protected reservoir of bacteria (Figs. 5 and 7). They may also enhance the development of antimicrobial resistance, especially in Gram-negative bacteria that acquire stepwise resistance mutations to concentration- dependent antibiotics. 188 T. Nuttall VetBooks.ir Table 3 First-line topical antimicrobials Fusidic acid Florfenicol Polymyxin B Gentamicin Neomycin Fluoroquinolones Nystatin Terbinafine Clotrimazole Miconazole Posaconazole Gram-positive only Effective against MRSA and MRSP Synergistic with framycetin against Gram-positive bacteria Broad-spectrum but not effective against Pseudomonas spp. Broad-spectrum and effective against Pseudomonas spp. Inactivated by organic debris and needs a clean ear canal Synergistic with miconazole against Gram-negative bacteria Broad-spectrum and effective against Pseudomonas spp. Broad-spectrum but limited efficacy against Pseudomonas spp. Broad-spectrum and effective against Pseudomonas spp. Additive activity with silver sulfadiazine against Pseudomonas spp. Broad-spectrum antifungals MRSA methicillin-resistant Staphylococcus aureus, MRSP methicillin-resistant S. pseudintermedius First-Line Antimicrobial Treatment In general, topical antimicrobials are more effective than oral antibiotics for resolving otitis externa (Table 3). High antimicrobial concentrations (usually mg/ml) can overcome apparent antibiotic resistance. It is important to use an adequate volume to penetrate into the ear canals – 0.5–1 ml is sufficient for most cats, but this may be too much in very small animals. The efficacy of concentration-dependent drugs (e.g. fluoroquinolones and aminoglycosides) depends on delivering concentrations of at least 10x MIC once daily. Time-dependent drugs (penicillins and cephalosporins) require concentrations above MIC for at least 70% of the dosing interval. This is readily obtained with topical therapy, which achieves high local concentrations that probably persist in the absence of systemic metabolism. Most topical medication should be effective with once daily dosing, although some are licensed for twice daily administration. Products licensed for use in dogs should be used with care in cats as ototoxicity is possible. Topical Antibiotic Treatment of Multi-drug-Resistant Bacteria If bacteria persist on cytology despite 1–2 weeks of appropriate treatment, then antibiotic resistance should be suspected. Other reasons for treatment failure include polyps, neoplasia, foreign bodies and other underlying conditions; debris, biofilms and failure to clean the ears; stenosis, otitis media and other perpetuating factors; and poor compliance. Pseudomonas are inherently resistant to many antibiotics, and they readily develop further resistance if treatment is ineffective. There are a variety of approaches to multi-drug-resistant infections (Table 4), although none of these are licensed in cats and they must be used with care. Otitis 189 Table 4 Antibiotics useful in multi-drug-resistant infections VetBooks.ir Antibiotic Ciprofloxacin Enrofloxacin Marbofloxacin Clavulanate– ticarcillina Ceftazidimea Silver sulfadiazine Amikacin Gentamicin Treatment regimes 0.2% sol. 0.15–0.3 ml/ear q 24 h 2.5% injectable sol. diluted 1:4 with TrizEDTA, saline or Epi-Otic® topically q 24h; 22.7 mg/ml sol. 0.15–0.3 ml/ear q 24 h 1% injectable sol. diluted 1:4 with saline or TrizEDTA topically q 24h; 2 mg/ml in TrizEDTA topically q 24h; 20 mg/ml sol. 0.15–0.3 ml/ear q 24h 16 mg/ml in TrizEDTA topically q 24h; reconstituted injectable sol. 0.15–0.3 ml/ear q 12h; 160 mg/ml sol. 0.15–0.3 ml/ear q 12h; potentially ototoxic 10 mg/ml in TrizEDTA topically q 24h; 100 mg/ml 0.15–0.3 ml/ear q 12h Dilute to 0.1–0.5% in saline; additive activity with gentamicin and fluoroquinolones 2 mg/ml in TrizEDTA topically q 24h; 50 mg/ml 0.15–0.3 ml/ear q 24h; susceptibility maintained if there is resistance to other aminoglycosides; potentially ototoxic 3.2 mg/ml in TrizEDTA topically q 24; ototoxicity possible but uncommon Reconstituted sol. Stable for up to 7 days at 4 °C or for 1 month frozen a Tris-EDTA Tris-EDTA damages bacterial cell walls and increases antibiotic efficacy, which can overcome partial resistance. It is best given 20–30 minutes before the antibiotic but can be co-administered. It is well tolerated and non-ototoxic. Tris-EDTA shows additive activity with chlorhexidine, gentamicin and fluoroquinolones at high concentrations [9, 10, 12]. Treatment of Biofilms and Mucus Biofilms can be physically broken up and removed by thorough flushing and aspiration. Topical Tris-EDTA and N-acetylcysteine (NAC) can disrupt biofilms, facilitating their removal, and enhancing penetration of antimicrobials. NAC, however, is potentially irritating (particularly in concentrations above 2%). Systemic NAC (600 mg orally twice daily) can help dissolve biofilms in the middle ear. Systemic NAC and bromhexine (1–2 mg/kg orally q12h) can liquefy mucus, facilitating drainage in otitis media due to chronic mucosal inflammation of inflammatory polyps (see below). Systemic Antimicrobial Therapy Systemic therapy may be less effective in otitis externa because bacteria are present only in the external ear canal and cerumen, there is no inflammatory discharge and penetration to the lumen is poor. Systemic treatment is indicated when the ear canal cannot be treated topically (e.g. stenosis or compliance problems or if topical VetBooks.ir 190 T. Nuttall adverse reactions are suspected) and in otitis media. High doses of drugs with good tissue penetration (e.g. clindamycin or fluoroquinolones) should be considered. Oral itraconazole (5 mg/kg orally once daily) can be administered if systemic antifungal therapy is indicated. Otitis Media Aetiology and Pathogenesis Otitis media may be primary or secondary. Inflammatory polyps (see below) are the most common cause of primary otitis media in cats. Chronic otitis externa can result in maceration and rupture of the tympanic membrane (Fig. 10), especially with stenosis of the horizontal ear canal and Gram-negative bacterial infections. Chronic upper respiratory infections lead to inflammation and increased bacterial colonisation of the nasopharynx, which may ascend up the Eustachian tube. Less commonly, infections may spread to the middle ear from retrobulbar or para-aural abscesses, or other severe local or systemic infections. Middle-ear infections may rupture through the tympanic membrane into the ear canal or spread to the para-aural tissues and/or central nervous system. Clinical Signs Clinical signs associated with otitis media can be chronic, mild and vague until neurological deficits become evident (Table 5) (Figs. 11 and 12). Fig. 10 Ruptured ear drum in cat with chronic upper respiratory tract and middle ear infections. The middle ear mucosa (A) is visible behind the malleus (B) Otitis 191 VetBooks.ir Table 5 Clinical signs associated with otitis media in cats Otitis media Head shaking, rubbing or scratching Dullness and pain; may avoid hard foods and handling around the head Reduced ability to localise sound (unilateral) Deafness (bilateral) Neurological deficits Horner’s syndrome (miosis, partial ptosis and apparent enophthalmos); sympathetic trunk Ataxia and nystagmus; peripheral vestibular syndrome Facial paresis; facial nerve Fig. 11 Head tilt in a cat with otitis media associated with a Pasteurella infection Diagnosis Using otoscopy and myringotomy to demonstrate an abnormal tympanic membrane and/or fluid or debris in the tympanic bulla is diagnostic. Imaging such as radiography, CT or MRI is useful when stenosis limits otoscopic examination and will reveal the extent of the otitis media and lytic, proliferative and/or expansive changes in the tympanic bulla. VetBooks.ir 192 T. Nuttall Fig. 12 Horner’s syndrome in a cat with otitis media caused by an inflammatory polyp Treatment Many cases of otitis media will resolve with medical therapy, but most cases will also require flushing of the middle ear. A myringotomy will be necessary if the tympanic membrane is intact. Systemic antibiotics should be selected based on bacterial culture of the middle ear, taking into account the ability of the antibiotic to penetrate the middle ear. Penetration of antibiotics into chronically inflamed ears could be poor, and high doses of drugs with a high volume of distribution (e.g. fluoroquinolones) should be considered [13]. Systemic therapy can be challenging if susceptibility is limited to topical and/or parenteral drugs. Topical antibiotics and glucocorticoids in saline or Tris-EDTA can be directly administered into the middle ear; gentamicin, fluoroquinolones, ceftazidime and dexamethasone do not appear to be specifically ototoxic when administered this way [5, 14]. It is unclear how long these drugs persist in the middle ear, but, as this is essentially a blind-ended sac, drugs are likely to be active in the middle ear for a few days. Repeated instillation of mg/ml solutions every 5–7 days could therefore be useful in multidrug-resistant infections that are refractory to oral medication. Treatment should continue until clinical resolution, which may take 6–8 weeks in severe cases. Oral or topical glucocorticoids and/or mucolytics should also be administered in appropriate cases. The tympanic membrane generally heals within 2–3 weeks if infection and inflammation are controlled. Chronic otitis media, osteomyelitis of the tympanic bulla, cholesteatoma and para-aural abscesses may be refractory to medical treatment. A total ear canal ablation/lateral bulla osteotomy is required in these cases. Otitis 193 VetBooks.ir Foreign Bodies Clinical Signs Potential foreign bodies include grass awns, hair and other organic debris, cotton wool, cotton bud tips and (occasionally) broken pieces from catheters or forceps. These cause variable, acute and sometimes extreme pain and pruritus. Some cases may present with chronic otitis externa that is poorly responsive to treatment. Most cases are unilateral but bilateral foreign bodies can be seen. Foreign bodies may penetrate the tympanic membrane and cause otitis media. Diagnosis Otoscopic examination will reveal variable amounts of inflammation and exudates. The nature of the exudate will depend on the secondary infection. Large foreign bodies are usually visible, but the cat may need to be sedated or anaesthetised to allow ear cleaning and complete visualisation of the ear canal. Advanced imaging may be needed to detect a foreign body that has penetrated fully into the middle ear. Treatment The foreign body must be removed using forceps and/or ear flushing. Care should be taken to check that it has been completely removed – tiny fragments left behind can be enough to perpetuate the problem. The inflammation and secondary infection should be treated appropriately (see above), but they normally quickly resolve once the foreign body has been removed. Inflammatory Polyps Aetiology and Pathogenesis Inflammatory polyps are a common cause of otitis media and externa in cats [15]. They are most common in young cats but can be seen in older individuals. Most are unilateral but they can be bilateral. Their aetiology is unknown but may involve an abnormal inflammatory reaction to the commensal nasopharyngeal microflora or to respiratory virus infections (although virus isolation has been negative) [16]. 194 T. Nuttall VetBooks.ir Clinical Signs The polyps usually arise in or near to the opening of the Eustachian tube [15]. They may extend down the Eustachian tube and into the nasopharynx, causing snoring, an altered voice, sneezing, coughing, gagging and/or retching. Polyps within the ear usually present with otitis media (if the tympanic membrane is intact; Fig. 12) and/ or otitis externa (if the tympanic membrane is ruptured and the polyp extends into the ear canals). This is usually associated with a secondary bacterial infection and a purulent discharge in the ear canals (Fig. 13). It is unusual for the polyp to extend in the ventro-medial compartment of the tympanic bulla. However, this is often full of mucus arising from obstruction of the Eustachian tube and draining foramen by the polyp and inflamed mucosa (Fig. 9). This can become stagnant, inspissated and/ or infected. Diagnosis A history of unilateral otitis, purulent discharge, Horner’s syndrome and/or otitis media is highly suggestive of an inflammatory polyp [15]. The polyp may be visible in the ear canal (after cleaning any discharge; Fig. 14) or in the nasopharynx (which usually requires sedation and pulling the soft palate rostrally). Diagnostic imaging can be used to confirm the extent and severity of the polyp and secondary infection. Computerized tomography (CT) has much better sensitivity and specificity than radiography. Density analysis of the pre- and post-contrast CT images weighted for bone and soft tissue will differentiate solid polyp tissue from fluid (mucus and/ or pus) and show areas of active inflammation or infection (Fig. 9). This allows Fig. 13 Waxy and suppurative debris in the ear canal of a cat with an inflammatory polyp. The polyp could not be seen until the debris was flushed away. Repeated courses of antibiotics had led to an MRSA infection VetBooks.ir Otitis 195 Fig. 14 Inflammatory polyp in the horizontal ear canal accurate assessment of the extent of the polyp; for example, while radiographs can suggest that all compartments of the middle ear are affected, a CT scan can show the true extent of the solid polyp, mucus build-up and involvement of the Eustachian tube. CT scans will also more accurately assess changes to the bony structures of the tympanic bulla and middle ear (e.g. osteomyelitis, sclerosis, proliferation and/ or lysis). This can be critical for planning treatment; for example, in most cases, CT scans show that solid polyps don’t extend into the ventral compartment, making a ventral bulla osteotomy unnecessary. Other types of tumours should be suspected if a polyp-like mass develops in older cats, and histopathology can be used to confirm the diagnosis. Treatment Polyps in the nasopharynx, dorsolateral middle ear and external ear canal can be removed via traction with forceps under anaesthetic [17, 18]. The polyp is grasped firmly with a set of forceps and gradual continuous traction applied to pull the polyp from the middle ear. They can usually be removed in one piece, but sometimes multiple attempts are needed (Fig. 15). Twisting the polyp stalk before or during traction can help limit bleeding. Small polyps in the horizontal ear canal can be removed using alligator forceps through an operating head or video otoscope. Flatter nodules that are difficult to grasp with forceps can be ablated with a laser (Fig. 16). Solid polyps in the ventro-medial bulla compartment have to be removed via a ventral bulla osteotomy, although this is uncommon. Otitis externa and media are often present, and material from the ear canals and middle ear should be collected for cytology and culture. The polyps themselves VetBooks.ir 196 T. Nuttall are invariably sterile. The ear canals and middle ear should be flushed and treated appropriately (see treatment of otitis externa and otitis media above). Systemic glucocorticoids (e.g. 2 mg/kg prednisolone or 0.2 mg/kg of dexamethasone daily to resolution and then slowly tapered) will reduce post-traction inflammation, help open the bulla foramen and Eustachian tube and may help to reduce the recurrence rate [19]. N-acetylcysteine (600 mg orally q12h) or bromhexine (2 mg/kg q12h) can help liquefy mucus and facilitate drainage from the middle ear. Fig. 15 Inflammatory polyp (see Fig. 14) after removal by traction. The intact stalk indicates that it has been successfully removed intact Fig. 16 (a) Sessile inflammatory polyps arising in the horizontal ear canal; (b) the horizontal ear canal following laser ablation of the polyps and ear flushing a Otitis b VetBooks.ir Fig. 16 (continued) 197 Potential complications include Horner’s syndrome, vestibular syndrome and facial nerve paralysis. Horner’s syndrome is particularly common as a sympathetic nerve trunk is very close to the most common origin of polyps near the opening of the Eustachian tube (Fig. 12). These problems are usually temporary, and permanent deficits are rare. Cystoadenomatosis (Cystomatosis) Aetiology and Pathogenesis Cystoadenomatosis results in multiple, pigmented, ceruminous papules, nodules and cysts in the ventral pinna and external ear canal [4, 5, 20]. The cause is unknown, but may involve genetic predisposition and inflammatory triggers. Persian cats may be predisposed. The cysts eventually block the ear canal resulting in otitis externa and secondary infections. Clinical Signs The clinical appearance is highly suggestive. Early cases present with multiple blue-black comedones and papules around the opening of the ear canal (Fig. 17). These gradually increase in number and size, forming nodules and cysts that may spread onto the pinna and into the vertical and (less commonly) horizontal ear canals (Fig. 18). Ruptured cysts release a brown-black fluid. Cysto adenomatosis is VetBooks.ir 198 Fig. 17 Multiple blue-black comedones and cysts on the pinna of a cat with cysto adenomatosis Fig. 18 Multiple cysts obstructing the ear canals in a cat with cysto adenomatosis T. Nuttall VetBooks.ir Otitis 199 not usually pruritic or painful unless secondary infections are present. Ceruminous adenomas and adenocarcinomas are more commonly seen in older animals and form solitary or small numbers of discreet tumours. Diagnosis The clinical appearance is largely pathognomonic. If necessary, histopathology will differentiate adenocarcinoma, adenoma and cysto adenomatosis. Ear cytology can be used to identify secondary Malassezia and/or bacterial infections. Advanced imaging can be performed if an otitis media is suspected. Treatment Medical treatment is suitable for early and/or mild cases. Any secondary otitis should be treated appropriately. Systemic and/or topical steroids can decrease swelling and ceruminous hyperplasia in the ears. Regular maintenance therapy with topical steroids can be used to maintain remission. More extensive nodules and cysts can be ablated with a CO2, diode or other laser, or electrocautery (Fig. 19). Topical antibiotics/steroid combinations should be used postoperatively to reduce inflammation and prevent infection. Laser ablation is very effective with prolonged remission. Regular topical steroids may reduce the recurrence rate. Fig. 19 Same cat as in Fig. 18; here the cysts have been ablated using a laser VetBooks.ir 200 T. Nuttall Total ear canal ablation with lateral bulla osteotomy is necessary in cases where medical therapy or laser ablation isn’t appropriate or available. Surgery is curative, although at the expense of the ear. Otodectes and Other Parasites Aetiology and Pathogenesis Otodectes cynotis mites are the most common cause of parasitic otitis, although others can include trombiculid mites (mainly on the pinnae), Demodex species (mainly on the pinnae and only rarely in the ear canals) and Otobius megnini (the spinose ear tick; very rare in cats). Otodectes are highly contagious between cats and other species, and are common in multi-cat situations (particularly with young animals and/or where there is a high turnover). Most Demodex are not contagious, although Demodex gatoi may be contagious between cats in a household. Clinical Signs Otodectes cynotis infestation is characterised by large amounts of dry, brown, waxy debris with variable erythema and pruritus (Fig. 20). The pruritus may be severe and extend onto the head and neck, making Otodectes a differential diagnosis in head and neck dermatitis. Cats can develop hypersensitivity reactions to Otodectes, and small numbers of mites can still be associated with clinical signs. Some cats are apparently asymptomatic carriers of Otodectes. Demodex species cause similar clinical signs. Otobius can result in a variably severe inflamed and painful otitis externa. Diagnosis The history and clinical signs are highly suggestive of Otodectes. Careful otoscopic examination often reveals the mites as they move (Fig. 21). Otodectes and Demodex can be seen on microscopic examination of the waxy debris broken up in liquid paraffin (Fig. 22). Treatment trials for Otodectes (see below) are warranted if mites aren’t found as small numbers can be missed in sensitised cats. Demodex may be found on hair plucks, tape strips or skin scrapes of the pinnae or elsewhere. Otobius ticks should be obvious on otoscopic examination. VetBooks.ir Otitis Fig. 20 Characteristic dry waxy discharge at the opening of the ear canal in a Persian cat with Otodectes Fig. 21 Otodectes seen in the ear canal using a video otoscope 201 VetBooks.ir 202 T. Nuttall Fig. 22 Adult Otodectes mite found by collecting the ear canal discharge into liquid paraffin (x100 magnification) Treatment Most anti-mite products are effective against Otodectes, including topical fipronil, selamectin and imidacloprid/moxidectin. Isoxazoline drugs seem to be highly effective against Otodectes and Demodex. All potentially exposed cats and dogs should be treated. Otobius ticks can be killed with an appropriate product before careful removal using forceps. Any secondary otitis usually resolves rapidly but can treated if necessary. Neoplasia Aetiology and Pathogenesis Ear canal neoplasia is fairly common in older cats. Most tumours are ceruminous adenomas, but malignant adenocarcinomas comprise up to 50% of ceruminous tumours [4, 5, 20]. Other tumours in the ear canals are rare. The obstruction usually results in a secondary otitis externa. Malignant tumours can result in local destruction and invasion and potentially spread to local lymph nodes and distal organs. Tumours arising from external tissues can occasionally invade the middle ear and/ or ear canals. Otitis 203 VetBooks.ir Clinical Signs Most tumours arise at the base of the pinna and upper vertical canal, although they can be seen at any depth in the ear canals. The nodules can be obscured by discharge if there is a secondary infection. Swelling of the surrounding tissues and/or local lymph nodes is suggestive of local spread and/or metastasis. Diagnosis The clinical presentation is usually obvious, although single lesions deeper in the ear canal should be distinguished from inflammatory polyps and multiple tumours from cysto adenomatosis. Cytology and/or histopathology can help differentiate neoplasia from polyps and benign from more malignant tumours (Fig. 23). Aspirates should be taken from local lymph nodes if there is any suspicion of malignancy or spread. Imaging (especially CT scans) can be used to determine the extent and severity of local invasion, lymph node involvement and metastasis to internal organs such as the lungs. Treatment Accessible benign tumours can be surgically excised. Lasers can be used to excise and ablate tumours deeper in the ear canals where surgical excision isn’t possible. Vertical ear canal surgery or total ear canal ablation can be used to remove tumours if lasers aren’t available or wider surgical margins are required (Fig. 24). The prognosis is good unless there has been metastatic spread. Fig. 23 Fine needle aspiration cytology from a ceruminous adenoma; there are numerous epithelial cells forming a well-defined and differentiated sheet with minimal pleomorphism VetBooks.ir 204 T. Nuttall Fig. 24 Benign ceruminous adenoma in the horizontal ear canal of a cat following a total ear canal ablation. A laser could have been used to ablate the tumour in situ and preserve the ear canal Seborrheic Otitis Seborrheic otitis is a common problem of uncertain aetiology and clinical significance [4, 5]. Dark waxy to greasy scales build up on the inside of the pinna and around the opening of the ear canal (Fig. 25). The lower vertical and horizontal ear canals are usually normal. The cats may have no other clinical signs but can shake their heads, flick their ears or scratch at their ears. This may be secondary to inflammation, and affected cats should be carefully evaluated for other clinical signs consistent with primary causes of otitis, which should be managed appropriately. Seborrheic otitis may be seen in Persian and related cats with idiopathic facial dermatitis. Sphynx and Devon rex cats can have VetBooks.ir Otitis 205 Fig. 25 Build-up of sebaceous/ceruminous material in the vertical ear canal. The focal accumulation of the material is suggestive of glandular hyperplasia or hypersecretion an asymptomatic build-up of cerumen on the inner pinnae. Cytology should be used to determine whether there is a bacterial or Malassezia infection. However, the waxy build-up may simply be material accumulating on the pinna after epidermal migration out of the ear canals. If there are no other clinical signs, the cats don’t need treatment. If necessary, gentle wiping with a ceruminosolvent/ceruminolytic ear cleaner can reduce the build-up. Proliferative and Necrotising Otitis Aetiology and Pathogenesis The aetiology of this condition is unknown, but it is probably immune-mediated [21, 22]. The lesions show T-cell-mediated keratinocyte apoptosis similar to erythema multiforme [22]. It was first recognised in kittens but has now been reported in adult and older cats, although most cases are seen in cats less than 4 years old [4, 5]. Clinical Signs The clinical signs are very suggestive. The lesions are usually symmetrical and most commonly affect the base of the pinna, opening of the ears and the vertical ear canal. Occasionally, the lips, face, periocular skin or remote sites may become involved. Affected cats develop erythematous and hyperkeratotic plaques with tightly adherent crusts. More severe cases may have erosions, ulceration and haemorrhage (Fig. 26). Secondary bacterial or Malassezia ear infections may obscure the clinical lesions. VetBooks.ir 206 T. Nuttall Fig. 26 Proliferative and necrotising otitis in a cat with erythematous plaques, erosions and crusts Diagnosis The diagnosis is usually based on the history and clinical signs. Cytology should be used to identify secondary infection, which should be treated appropriately [21]. Where necessary, cytology and histopathology can be used to confirm the diagnosis and eliminate differential diagnoses affecting the pinna and ear canals such as pemphigus foliaceus, eosinophilic granuloma syndrome and thiamazole-associated drug reactions. Treatment The prognosis is generally good [21]. Many cases, especially in kittens or young cats, may spontaneously resolve. There is usually a good response to topical 0.1% tacrolimus or systemic ciclosporin. Some cats may not need further treatment after resolution, but some may need long-term therapy to maintain remission. Otitis 207 VetBooks.ir Para-aural Abscessation Para-aural abscesses are uncommon in cats. Causes include severely infected otitis externa and/or media that extends into the surrounding soft tissues, bite wounds, deep bacterial, mycobacterial and/or fungal infections, complications from ear canal and/or middle ear surgery, and traumatic ear canal avulsion (usually following a road traffic accident) (Fig. 27). Advanced imaging (especially contrast-enhanced CT scans) can reveal the extent and severity of the infection and inflammation, including sinus tracts into adjacent structures and tissues (which can include the central nervous system). Samples for cytology and culture should be taken from the affected tissues (Fig. 28), as secondary bacterial infections on the surface may obscure the causative organisms. This may require surgical exploration. Treatment depends on the primary cause and may include surgical exploration, debridement and flushing, vertical ear canal surgery or a total ear canal ablation/ lateral bulla osteotomy. Surgical sites, sinus tracts and debrided tissues should be thoroughly flushed. Drains may be necessary with deep abscesses or sinus tracts. Antimicrobials should be selected using culture and administered until clinical cure. The course of treatment will depend on the extent and severity of infection Fig. 27 Extensive para-aural abscesses, ulcers and sinus tracts in a cat with an Actinomyces infection following a bite wound VetBooks.ir 208 T. Nuttall Fig. 28 Deep tissue cytology from the cat in Fig. 27. There is pyogranulomatous inflammation with a prominent multinucleated giant cell. This has several beaded filamentous organisms characteristic of Actinomyces and inflammation. Prolonged courses aren’t necessary after surgery provided that the site is clean and closed well, but longer courses (4–6 weeks or longer) will be necessary with deep infections (especially with slow growing organisms such as Nocardia, Actinomyces, mycobacteria and fungi). References 1. 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A comparison of the rostrocaudal open mouth and rostro 10 degrees ventro-caudodorsal oblique radiographic views for imaging fluid in the feline tympanic bulla. Vet Radiol Ultrasound. 2005;46:205–9. 7. Nuttall TJ, Cole LK. Ear cleaning: the UK and US perspective. Vet Dermatol. 2004;15:127–36. 8. Swinney A, Fazakerley J, McEwan N, Nuttall T. Comparative in vitro antimicrobial efficacy of commercial ear cleaners. Vet Dermatol. 2008;19:373–9. 9. Buckley LM, McEwan NA, Nuttall T. Tris-EDTA significantly enhances antibiotic efficacy against multidrug-resistant Pseudomonas aeruginosa in vitro. Vet Dermatol. 2013;24:519. 10. Clark SM, Loeffler A, Schmidt VM, Chang Y-M, Wilson A, Timofte D, et al. Interaction of chlorhexidine with trisEDTA or miconazole in vitro against canine meticillin-resistant and -susceptible Staphylococcus pseudintermedius isolates from two UK regions. Vet Dermatol. 2016;27:340–e84. VetBooks.ir Otitis 209 11. Pye CC, Yu AA, Weese JS. Evaluation of biofilm production by Pseudomonas aeruginosa from canine ears and the impact of biofilm on antimicrobial susceptibility in vitro. Vet Dermatol. 2013;24:446–E99. 12. Pye CC, Singh A, Weese JS. Evaluation of the impact of tromethamine edetate disodium dihydrate on antimicrobial susceptibility of Pseudomonas aeruginosa in biofilm in vitro. Vet Dermatol. 2014;25:120. 13. Cole LK, Papich MG, Kwochka KW, Hillier A, Smeak DD, Lehman AM. Plasma and ear tissue concentrations of enrofloxacin and its metabolite ciprofloxacin in dogs with chronic end-stage otitis externa after intravenous administration of enrofloxacin. Vet Dermatol. 2009;20:51–9. 14. Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract. 2018;59:10–5. 15. Greci V, Mortellaro CM. Management of Otic and Nasopharyngeal, and nasal polyps in cats and dogs. Vet Clin North Am Small Anim Pract. 2016;46:643. 16. Veir JK, Lappin MR, Foley JE, Getzy DM. Feline inflammatory polyps: historical, clinical, and PCR findings for feline calici virus and feline herpes virus-1 in 28 cases. J Feline Med Surg. 2002;4:195–9. 17. Greci V, Vernia E, Mortellaro CM. Per-endoscopic trans-tympanic traction for the management of feline aural inflammatory polyps: a case review of 37 cats. J Feline Med Surg. 2014;16:645–50. 18. Janssens SDS, Haagsman AN, Ter Haar G. Middle ear polyps: results of traction avulsion after a lateral approach to the ear canal in 62 cats (2004–2014). J Feline Med Surg. 2017;19:803–8. 19. Anderson DM, Robinson RK, White RAS. Management of inflammatory polyps in 37 cats. Vet Rec. 2000;147:684–7. 20. Sula MJM. Tumors and tumorlike lesions of dog and cat ears. Vet Clin North Am Small Anim Pract. 2012;42:1161. 21. Mauldin EA, Ness TA, Goldschmidt MH. Proliferative and necrotizing otitis externa in four cats. Vet Dermatol. 2007;18:370–7. 22. Videmont E, Pin D. Proliferative and necrotising otitis in a kitten: first demonstration of T-cell- mediated apoptosis. J Small Anim Pract. 2010;51:599–603. VetBooks.ir Part III Feline Skin Diseases by Etiology VetBooks.ir Bacterial Diseases Linda Jean Vogelnest Abstract Accurate diagnosis of feline bacterial skin diseases is important for both patient well-being and appropriate use of antibiotics in times of increasing antimicrobial resistance. This chapter reviews knowledge of clinical lesions and historical features associated with feline bacterial infections, skin diagnostics relevant to efficient and accurate diagnosis, and current treatment recommendations. Deep infections including nocardiosis and mycobacteriosis (Chapter, Mycobacterial Diseases) are well-reported, and although accurate diagnosis is important, and treatment may be lengthy and challenging, they do occur only rarely. In contrast, superficial bacterial pyoderma (SBP) is a more common feline presentation that may be under-recognised, most typically complicating underlying allergic skin disease, but also associated with a range of underlying diseases and factors. SBP is reviewed in this chapter, along with deeper infections including deep bacterial pyoderma, cellulitis and wound abscessation, dermatophilosis, necrotizing fasciitis and environmental saprophytic bacterial infections including nocardiosis. Confirmation of bacterial skin disease in cats is readily achievable in a general practice setting. Cytology is often the most valuable tool, used in conjunction with clues from the history and physical examination and supplemented with skin surface or tissue culture and/or histopathology when indicated. Cytology methods relevant to bacterial infections in the cat are detailed in this chapter. Treatment principles are also discussed, including the potential role of methicillin- resistant staphylococci in feline pyoderma, with a focus on current worldwide recommendations that may supersede some outdated clinic protocols. L. J. Vogelnest (*) University of Sydney, Sydney, NSW, Australia Small Animal Specialist Hospital, North Ryde, NSW, Australia e-mail: lvogelnest@sashvets.com © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_11 213 214 L. J. Vogelnest VetBooks.ir Introduction Bacterial dermatoses in the cat occur in two broad presentations reflecting the depth of skin invasion. Superficial infections, involving the epidermis and follicular epithelium, are most common and primarily associated with multiplication of resident skin microbiota secondary to reduced local and/or systemic host defences. Deep bacterial infections, involving the dermis and/or subcutaneous tissues, may be extensions of superficial infection or associated with traumatic implantation of a range of environmental or commensal bacterial species. Some rare but life-threatening deep bacterial infections have a propensity for body dissemination. Normal Feline Cutaneous and Mucosal Bacterial Microbiota There is limited knowledge about normal commensal bacteria in cats, with most studies culture-based and focused on staphylococcal isolates. The mouth, followed by the perineum, appears to be the most consistent staphylococcal carriage site [1]. Fifteen species of staphylococci were identified by MALDI-TOF testing of isolates from the oropharynx of healthy cats in Brazil, with S. aureus the only coagulase- positive staphylococcus (CoPS) species, with a range of coagulase-negative staphylococci (CoNS) [2]. However, α-haemolytic streptococci were more frequently isolated than staphylococci from healthy mouths of free-roaming cats in Spain, followed by two Proteobacteria (Neisseria spp. and Pasteurella spp.) [3]. Staphylococci have also been less frequently identified as resident skin bacteria in normal cats, with Micrococcus spp., Acinetobacter spp. and Streptococcus spp. most common [4]. Of staphylococci isolated, CoNS including S. felis, S. xylosus and S. simulans have been more frequent than CoPS [4–6], with S. felis potentially misidentified as S. simulans in some studies [5, 7]. Either S. intermedius (reclassified as S. pseudintermedius in 2005) [1, 8] or S. aureus [5, 9, 10] are variably reported as the more frequent CoPS isolates. Escherichia coli, Proteus mirabilis, Pseudomonas spp., Alcaligenes spp. and Bacillus spp. are less frequent isolates from normal feline skin [4, 5]. More recent genomic DNA studies in healthy cats (n = 11) identified a greater diversity and number of bacteria on normal feline skin than culture-based studies. Haired skin had the greatest diversity of species, the pre-aural space the greatest richness and evenness of species, and mucosal surfaces (nostril, conjunctiva, reproductive) and the ear canal (contrasting to dogs) the lowest species diversity. As for culture-based studies, Staphylococcus spp. did not dominate, with Proteobacteria (Pasteurellaceae, Pseudomonadaceae, Moraxellaceae [e.g. Acinetobacter spp.]) most frequent, followed by Bacteroides (Porphyromonadaceae), Firmicutes (Alicyclobacillaceae, Staphylococcaceae, Streptococcaceae), Actinobacteria (Corynebacteriaceae, Micrococcus spp.) and Fusobacteria. It is acknowledged that some species including Propionibacterium spp. may have been under-recognised in this study [11]. VetBooks.ir Bacterial Diseases 215 Bacterial residents vary between individuals [4, 11] and may also vary between healthy and diseased states. Carriage of staphylococci is known to increase in humans and dogs with atopic dermatitis. Similarly, Staphylococcus spp. were more frequently detected in allergic cats (n = 10) compared to normal healthy cats, with more dominance at some anatomic sites (e.g. ear canal) [11]. Staphylococcus spp. were also more prevalent in diseased mouths compared to normal mouths [3]. In contrast, there was no statistical difference in isolation of Staphylococcus spp. in another study (n = 98) from healthy skin compared to inflamed skin [9]. In summary, the feline studies to date suggest, in contrast to dogs, that Proteobacteria including Acinetobacter spp., Pasteurella spp. and Pseudomonas spp. are more common on normal feline skin than Staphylococcus spp., and amongst staphylococci, that CoNS appear to dominate. It is uncertain if staphylococci in general, and CoPS or CoNS in particular, multiply more readily on diseased skin. Superficial Bacterial Pyoderma Feline superficial bacterial pyoderma (SBP) is increasingly recognised and reported in 10–20% of cats presenting to dermatology referral [12–14]. As in other species, SBP in cats is a secondary disease, most commonly reported with hypersensitivities [12–14]; 10% of cats presenting to referral in the USA [14] and 60% in Australia had confirmed underlying allergy, most commonly atopic dermatitis [13]. Recurrent pyoderma is also commonly reported [13, 15]. Bacterial Species Although Staphylococcus spp. are considered the likely pathogens [1, 2, 9, 12], weaker adherence of S. pseudintermedius and S. aureus to normal feline corneocytes in contrast to canine and human corneocytes has been documented [16], and the casual bacterial species in feline SBP have only been confirmed in a small number of cats. S. aureus was isolated in pure culture from papules and crusts of one cat, with concurrent neutrophils on skin cytology, and complete resolution of lesions by 10 days of antibiotic therapy [17]. S. felis was isolated from the nostrils and skin lesions (excoriations) of another cat with suspected underlying flea bite hypersensitivity, with concurrent neutrophils and intracellular cocci on cytology, and complete resolution of lesions by 14 days of antibiotic therapy and flea control [5]. Eosinophilic granuloma complex lesions may also be complicated by secondary pyoderma, and the most common isolates from surface swabs and/or tissue biopsies from eosinophilic plaques or lip ulcers (n = 9), with concurrent neutrophils and intracellular cocci on cytology, were S. pseudintermedius and S. aureus. Other isolates detected in this study included CoNS, Pasteurella multocida, Streptococcus canis and Pseudomonas aeruginosa [12]. VetBooks.ir 216 L. J. Vogelnest A number of other bacterial culture studies, predominantly on laboratory isolates from a range of skin lesions unconfirmed as pyoderma, have focused on staphylococci; whether isolates were pathogenic or incidental is uncertain, and non- staphylococcal isolates are rarely reported [4, 7, 9, 17–19]. CoNS are the most common isolates in a number of studies, accounting for 96% of isolates from ‘inflamed skin’ (n = 24) [9], the second most frequent isolate (S. simulans) from abscesses, miliary dermatitis, excoriations, exfoliative dermatitis or eosinophilic plaques (n = 45) [17] and the most frequent isolates (S. felis followed by S. epidermidis) from unspecified ‘dermatitis’ [7]. Less common CoNS isolates include S. hyicus, S. xylosus and S. schleiferi subsp. schleiferi [9, 17]. CoPS have been more prevalent in some studies on diseased feline skin [4], with S. aureus (n = 69) [9, 17] or S. intermedius (n = 9 [5]; n = 30 [20]) the most frequent isolates, and Streptococcus spp. (10%), Proteus spp. (10%), Pasteurella spp. and Bacillus spp. (10%) also reported [20]. The relative importance of staphylococci in general, and CoNS and CoPS in particular, to feline pyoderma and whether there is one predominant causal species as for bacterial pyoderma in humans (S. aureus) and dogs (S. pseudintermedius) is currently uncertain. Clinical Presentation A median age of onset of 2 years is documented for feline SBP, although a wide range is reported (6 months to 16.5 years), with older cats also frequently affected (first presentation at >9 years of age in 23% of cats) [13]. Pruritus is common, particularly with underlying hypersensitivity, reported in 92% of cats with SBP in Australia and often severe (56%) [13]. Lesions associated with feline SBP often reflect self-trauma, consisting most typically of multifocal, crusted, alopecic, excoriated and erosive to ulcerative lesions (Figs. 1, 2, 3 and 4). Eroded papules, eosinophilic plaques, eosinophilic granulomas and rare pustules are also reported. The most frequent lesional sites are the face, neck, limbs and ventral abdomen [12, 13, 21]. Diagnosis Although some clinical lesions have been recognised as useful diagnostic clues for bacterial pyoderma in dogs [22, 23], SBP lesions in cats are less characteristic, with many non-specific presentations (e.g. erosions, crusting). Diagnostic tests are thus important to confirm a diagnosis of feline pyoderma (see later section on “Cytology”, Table 1) and are strongly encouraged prior to consideration of treatment with systemic antimicrobials [22–24]. Cytology has been considered the most useful single test, with the presence of neutrophils and intracellular or associated bacteria being diagnostic (Fig. 11a) VetBooks.ir Bacterial Diseases 217 Fig. 1 Feline secondary bacterial pyoderma (SBP): exudative erosions and crusting Fig. 2 Feline SBP: alopecia, erythema and focal crusting [12, 13, 22, 25]. In canine pyoderma, cytology is considered mandatory when typical lesions (pustules) are not present or scant and is also essential to identify concurrent or alternate Malassezia dermatitis [23]. The morphology of bacteria on cytology (cocci and/or rods) will also guide valid empirical treatment choices and/ or the need for bacterial culture. Adhesive tape impressions are applicable to all superficial skin lesions, in particular dry lesions and restricted body sites, while glass slide impressions are suitable for erosive to ulcerative lesions [22]. In canine SBP, it is reported that inflammatory cells and bacteria may be absent or scarce with concurrent immunosuppression from disease or drugs [23]. Histopathology is infrequently discussed in relation to diagnosis of SBP; however, it can provide further diagnostic confirmation, especially if samples are VetBooks.ir 218 L. J. Vogelnest Fig. 3 Feline SBP: erythematous eroded plaques Fig. 4 Feline SBP: well-demarcated alopecia and erythema with focal crusting collected without prior skin surface cleansing or disinfection as bacterial colonies are frequently observed within the crusts (Fig. 5) (see later section on Histopathology). Histopathology is also valuable to aid exclusion of other differentials for atypical presentations or when a diagnosis is uncertain [22]. Bacterial culture is not helpful for diagnosis of SBP, particularly when assessed independently of cytology, as isolation may simply reflect normal commensal species not involved in disease (see later section on Bacterial Culture) [6]. A heavy pure culture of one bacterial species is more likely associated with a pathogen than mixed-species isolation, but concurrent cytology remains essential [1]. Coagulase status of any staphylococci isolated is less helpful for feline pyoderma, as both CoNS and CoPS are potentially pathogenic. Despite a limited role diagnostically, culture and antibiotic susceptibility testing (C&S) can be important to guide appropriate antibiotic therapy, particularly when antimicrobial resistance is more likely. Bacterial Diseases 219 VetBooks.ir Table 1 Differential diagnoses and valuable diagnostic tools for cutaneous lesions associated with bacterial infections in cats Less common differentials for lesion Ectoparasites (Otodectes, larval ticks, trombiculids); pemphigus foliaceus Lesion Papules Common differentials SBP, allergya dermatophytosis Alopecia, erythema, scaling, crusting SBP, dermatophytosis, allergya, actinic keratoses (nonpigmented skin) Demodicosis (D. gatoi, D. cati), pemphigus foliaceus, ectoparasites (Cheyletiella, lice) Erosion, ulceration, crusting SBP, allergya, SCC (non-pigmented skin) Herpes viral dermatitis, SCC in situ, cutaneous vasculitis Erythematous plaques SBP, allergya Cutaneous xanthoma Nodules (lip, chin, linear) Nodules (poorly demarcated) Nodules (discrete) SBP, DBP, allergya Mycetoma, neoplasia (SCC) Mycobacteria, Nocardia, sterile panniculitis Pustules (rare) SBP, pemphigus foliaceus Bacterial cellulitis/ abscessation Neoplasia (variety), eosinophilic granuloma Pseudomycetoma (bacterial, dermatophyte), mycetoma, histiocytosis, sterile pyogranuloma Dermatophytosis Diagnostic tools History (parasiticides, exposure/contagion), cytology (tape impression), biopsy (histo) History (potential exposure/contagion, pruritus or lesions first), cytology (tape impression), biopsy (histo) History (degree of pruritus, recurrent/ seasonal), cytology (tape or slide impression), biopsy (histo) Cytology (tape or slide impression), biopsy (histo) Cytology (FNA), biopsy (histo) Cytology (FNA), biopsy (histo, C&S) Cytology (FNA), biopsy (histo, C&S) Cytology (impression after rupture), biopsy (histo) Atopic dermatitis, adverse food reactions and/or flea bite hypersensitivity C&S culture and antibiotic susceptibility testing, DBP deep bacterial pyoderma, FNA fine needle aspirates, histo histopathology, SBP superficial bacterial pyoderma, SCC squamous cell carcinoma a Treatment There are limited studies evaluating treatment of feline SBP, and most recommendations are anecdotal. However, recent guidelines stress the importance of confirming a diagnosis of SBP prior to considering systemic antibacterial therapy (see later section on Antibiotic Stewardship (Box 1)) [1, 22, 23]. Over-utilisation of antibiotics without confirmation of diagnosis is well-recognised, and the common practice of prescribing antibiotics ‘just in case’ is strongly discouraged [22–24, 26]. Topical antiseptic therapy is a more valid ‘just in case’ choice; however, prior cytology is always recommended [1]. VetBooks.ir 220 L. J. Vogelnest Fig. 5 Bacterial colonies, usually cocci, are frequently observed in biopsies from feline cutaneous lesions with secondary bacterial infection (H&E, 400×). (Courtesy of Dr. Chiara Noli) Topical Therapy Although cats are often considered less tolerant of topical therapies, and even in dogs topical therapy is considered under-utilised [23], topical therapy has been recommended as the optimal sole antibacterial treatment for superficial infections whenever achievable for the pet and owner, particularly for localised or mild lesions. It is also recommended as the best option for pyoderma associated with methicillin-resistant staphylococci (MRS) [1]. Topical therapy has the advantage of more rapid lesion resolution, reduced duration of systemic antibiotics, physical removal of bacteria and debris from the skin surface and reduced impact on bystander commensals [1, 23]. The response in dogs with SBP to daily chlorhexidine spray (4%) for 4 weeks concurrently with twice weekly bathing with chlorhexidine shampoo was comparable to oral amoxicillin-clavulanic acid (amoxi-clav) [27]. Other small studies have similarly shown sole topical therapy to be effective [1]. Although a range of topical formulations are discussed for use in dogs, it is acknowledged there is limited evidence for efficacy and safety to guide optimal choices and protocols [23]. There is even less evidence in cats. However, the author has found a range of topical antiseptics and antibiotics helpful in the treatment of SBP in some cats, particularly for localised lesions. Chlorhexidine solution (2–3% VetBooks.ir Bacterial Diseases 221 Box 1: Important Principles of Treatment for Cutaneous Bacterial Infections in Cats in Line with Good Antimicrobial Stewardship • Have sufficient evidence to confirm a diagnosis of bacterial infection prior to instigating treatment (unless severe and life-threatening): Avoid ‘just-in- case’ usage. –– Cytology is essential; culture of bacteria from a skin surface swab does not confirm infection. • Choose antibiotics wisely, based on recommended treatment guidelines: –– Use first-line antibiotics for empirical use, assuming relevant options exist for the confirmed infection. –– Only use second-line antibiotics if adverse events limit use of first-line choices and if culture and sensitivity testing (C&S) supports efficacy. –– Do not use third-line antibiotics (e.g. cefovecin, fluoroquinolones) unless C&S indicates absence of other first- or second-line choices: Avoid justification due to ‘ease of use’ without actively discussing first- line oral alternatives. • Use correct dose and duration of treatment: –– Dose at the upper end of dose range as skin blood supply is comparatively poor, and weigh patients: slightly over-dose rather than under-dose. –– Follow duration guidelines for the confirmed infection, and re-evaluate clinical and cytological response prior to cessation of therapy. once or twice daily), silver sulfadiazine 1% cream or mupirocin 2% ointment (twice daily) have apparent efficacy and safety [12, 13], and fusidic acid 1% viscous eye drops (Conoptal®; twice daily) may also be useful, particularly for facial/periocular lesions. Concern has been raised over the use of both mupirocin and fusidic acid in veterinary patients, potentially encouraging resistance in resident human staphylococci, and it has been recommended to restrict their use to cases without other practical choices [1, 23]. Shampoo therapy (chlorhexidine or piroctone olamine) once to twice weekly may be adjunctive for treatment or to inhibit recurrence of SBP, although it is poorly tolerated in many cats. Excessive grooming and exacerbated self-trauma in response to topical therapies in cats, especially to ointments or creams, may sometimes limit their use. Body suits or conforming bandages may be helpful, particularly in cats with severe pruritus. Despite a common concern of owners that licking will remove topical medications, there is no evidence to confirm that grooming notably reduces efficacy of topical therapy, as lipophilic medications will be quickly absorbed after application. Systemic Therapy There is a lack of consensus on the most appropriate systemic antibiotics for treatment of SPB and some variation in recommendations with geographical region [23, 28]. First-line antibiotics are considered suitable choices for empirical therapy, VetBooks.ir 222 L. J. Vogelnest assuming a diagnosis is confirmed (e.g. intracellular cocci on cytology). Culture and antibiotic susceptibility testing (C&S) is important for cases that respond poorly to appropriate empirical therapy, or if there is higher risk of MRS (repeated antibiotic courses, other household pet carriers, some geographical regions) [1, 12]. Amoxi-clav and cephalexin are generally considered first-line choices for feline SBP (see later section on Antibiotic Stewardship) [12, 13]. Amoxi-clav was effective for eosinophilic plaques and partially effective for lip ulcers with concurrent bacterial infection [25]. Doxycycline is used in some countries for first-line therapy of SBP, but resistance in some geographical regions [29], and potential value for MRS and multidrug-resistant staphylococci in others [10], suggests it may be less appropriate for first-line use. There is also debate over the use of cefovecin as first- line treatment for feline SBP, and although it is commonly adopted, third-generation cephalosporins are considered critically important antibiotics in human medicine, reserved for life-threatening diseases [26, 30–32]. It has thus been recommended cefovecin is not appropriate for first-line treatment for feline SBP, unless, due to compliance issues, no other treatment is possible. Second-line antibiotics may be considered if first-line antibiotics are not effective or serious side effects (real or potential due to previous history) limit the use of first-line choices. The major second-line choices for feline SBP are clindamycin or doxycycline, with preceding C&S optimal as efficacy is less predictable than for first-line choices (see later section on Antibiotic Stewardship). Lower sensitivity of staphylococcal isolates has been documented to clindamycin compared to amoxi-clav and cephalexin in South Africa [8] and to erythromycin in Malaysia [29]. Cefovecin is another potential second-line choice, when all avenues of oral administration of first-line and initial second-line choices have been exhausted. Second-generation fluoroquinolones (FQ) (enrofloxacin, marbofloxacin) are a final consideration, but restriction to cases with no other alternatives based on C&S is recommended. Ease of administration of FQ and low incidence of side effects are not justification for their use as first-line or early second-line options. Third-line antibiotics are rarely indicated for feline SBP, with topical therapies, even requiring hospitalisation and/or sedation where necessary, preferable. They include third-generation FQ (orbifloxacin, pradofloxacin), aminoglycosides (amikacin, gentamicin) and rifampicin. Critical antibiotics, reserved for life-threatening infections in humans, with veterinary use discouraged, are not a consideration for treatment of SBP in any species (see later section on Antibiotic Stewardship). Duration of Therapy Although there is an absence of scientific evidence to confirm an optimal duration of therapy for SBP in either dogs or cats, current expert opinion recommends a 3-week therapy as most appropriate [1, 26]. Shorter courses may be considered, until clinical lesions and microbiological evidence of infection have resolved; however, re-evaluation of patients is essential to make this assessment [1, 28]. VetBooks.ir Bacterial Diseases 223 reatment of the Primary Disease T It is well-recognised that the underlying primary cause of SBP must be managed to limit recurrence. However, there is less clarity on whether treatment of SBP and primary diseases need to occur concurrently or sequentially. As immunosuppressive therapy is contraindicated when treating infectious diseases, as a general rule, it is advised that SBP treatment be completed, prior to commencing any sustained glucocorticoid therapy (e.g. for primary allergy). In some cases of very active primary disease, resolution of SBP may not readily occur until the primary disease is more controlled. Management of primary atopic dermatitis in particular can be very challenging in some cats prone to secondary bacterial infections [13]. Ciclosporin therapy may be a more valid allergy treatment choice than glucocorticoids in this scenario, sparing innate immune responses (neutrophils, macrophages), albeit with slower onset of effect. Deep Bacterial Infections Chin Nodular Swelling: Secondary Deep Bacterial Pyoderma Feline chin acne most typically presents with brown to black comedones and hair casts on the ventral chin and occasionally the margins of the lower or upper lips (Chapter, Idiopathic Miscellaneous Diseases). A proportion of affected cats develop notable swelling with draining tracts, often due to secondary deep bacterial infection. Of cats with feline acne presenting to referral hospitals in the USA, 42% had deep bacterial infection (n = 72) [33], and 45% had bacteria isolated from tissue cultures (n = 22), including all cats with evidence of folliculitis and furunculosis on histopathology. The most frequent bacteria isolated, typically in pure culture, were CoPS, followed by α-haemolytic streptococci, Micrococcus sp., E. coli and Bacillus cereus. Of note, Pseudomonas aeruginosa was isolated in heavy growth from the tissue biopsy of one healthy control cat [34]. Clinical Presentation Deep pyoderma typically presents with large papules to nodular swelling with draining tracts (Fig. 6) and less commonly diffuse swelling. Lesions may be pruritic and/or painful, and regional lymph node enlargement can occur [3, 33, 34]. Diagnosis Cytology from fine needle aspirates (FNA) or expressed discharge after initial surface cleansing may reveal intracellular bacteria within neutrophils and/or macrophages. Careful examination may be required as bacteria can be sparse in samples from nodular lesions despite marked inflammation. Histopathology will typically reveal folliculitis, furunculosis and perifollicular to nodular pyogranulomatous inflammation (Fig. 7); bacteria present within follicular ostia or lumina in this setting, at least focally, confirm a diagnosis. Feline acne VetBooks.ir 224 L. J. Vogelnest Fig. 6 Feline chin acne: nodular swellings and drain tracts as a consequence of a deep bacterial infection. (Courtesy of Dr. Chiara Noli) Fig. 7 Histopathological section from feline chin acne (H&E, 40×): multifocal nodular pyogranulomatous inflammation in the mid and deep dermis, mostly centred on the hair follicles, which appear completely destroyed. Haemorrhage is evident, which is reflected clinically by haemopurulent exudate. (Courtesy of Dr. Chiara Noli) is associated with a spectrum of histopathology changes, with periglandular and/ or perifollicular inflammation usually dominating. Sebaceous gland ductal dilation and pyogranulomatous inflammation of sebaceous glands are also reported [34]. VetBooks.ir Bacterial Diseases 225 The presence of folliculitis and furunculosis without causal bacteria is suggestive of a role for secondary bacterial pyoderma, but exclusion of other causes including dermatophytosis is important, and special stains are warranted. Bacterial culture of sterile tissue biopsies or FNA from affected regions is required to identify causal species and enable antibiotic susceptibility testing. Treatment Systemic antibiotics are indicated; if intracellular cocci are evident on cytology, empirical treatment with cephalexin or amoxi-clav is often considered suitable. If bacterial rods are present on cytology, or in geographical regions where MRSP is more common, C&S is recommended, optimally from tissue biopsies. The optimal duration of therapy for deep pyoderma is undetermined; however, a minimum of 4–6 weeks is often advised, continuing for at least 2 weeks beyond resolution or stasis of lesions [1, 26]. Comedones typically persist in feline acne following resolution of the bacterial infection, so further treatment of the underlying pathology is important to limit recurrent infection (Chapter, Idiopathic Miscellaneous Diseases) [33]. Discrete Nodules: Bacterial Pseudomycetoma Some bacteria rarely cause localised discrete deep infections forming skin nodules that mimic fungal or neoplastic causes. Infections presumably occur following traumatic implantation of bacteria, which are most commonly Staphylococcus spp., but may be Streptococcus spp., Pseudomonas spp., Proteus spp. or Actinobacillus species. Clinical Presentation Single or multiple inflammatory nodules, with or without draining tracts, are typical. Discharge may contain small white grains or granules, composed of compact bacterial colonies [35]. A single case with less typical overlying thick crusting is reported in an FIV-positive cat, with concurrent SBP supported by cytology findings [36]. Diagnosis Cytology of FNA from intact nodules or impression smears of freshly expressed exudate should reveal numerous bacteria, most typically cocci but dependent on causal species. Histopathology will reveal nodular to diffuse pyogranulomatous dermatitis and/or panniculitis with numerous macrophages, multinucleate giant cells and central aggregations of bacteria, often with a brightly eosinophilic amorphous periphery (Splendore-Hoeppli phenomenon) (Figs. 8 and 9) [35, 36]. Treatment Surgical excision/drainage is important for resolution, as systemic antibiotics will often not penetrate into the central walled-off bacteria. VetBooks.ir 226 L. J. Vogelnest Fig. 8 Histopathological section from a lesion of bacterial pseudomycetoma (H&E 40×). There is a multifocal nodular pyogranulomatous inflammation with large bacterial colonies covered by bright red proteinaceous material, which appear clinically as white granules in the exudate. (Courtesy of Dr. Chiara Noli) Fig. 9 A bacterial colony (dark blue in the centre, is surrounded by amorphous eosinophilic material (Splendore-Hoeppli phenomenon) (H&E, 400×). (Courtesy of Dr. Chiara Noli) ubcutaneous Nodular Swellings with Abscessation: Anaerobic S Bacteria Painful rapidly progressing subcutaneous swellings are common in cats due to implantation of anaerobic bacteria, most typically associated with fight wounds although less commonly with other skin trauma including surgical wounds or catheterisation. Causal bacteria are often anaerobic or facultatively anaerobic oral commensals, including Pasteurella multocida, Fusobacterium spp., Peptostreptococcus spp., Porphyromonas spp. and gas-producing species such as Clostridium spp. and Bacteroides species [37]. VetBooks.ir Bacterial Diseases 227 Fig. 10 Swelling, ulceration, fistulisation and necrosis of the abdominal skin of a cat due to infection with anaerobic bacteria. (Courtesy of Dr. Chiara Noli) Clinical Presentation Poorly demarcated areas of oedema and swelling are typical, which progress to abscessation (Fig. 10) and sometimes overlying skin necrosis. Lesions are often single, but may be multiple, and are usually painful. There is often associated pyrexia and malaise, especially with larger lesions or when bacteria produce toxins. Purulent abscess contents often have a putrid smell, and tissue crepitus may be apparent. Diagnosis The clinical presentation is usually diagnostic. Cytology of abscess contents, or FNA from oedematous areas in early lesions, should reveal intense neutrophilic inflammation, with bacterial rods and/or cocci often readily apparent. Mixed infections are not unusual. Culture is generally not required, but anaerobic sampling would be important to accurately identify most causal bacteria. Treatment Early lesions are usually managed successfully with systemic antibiotics, with most organisms sensitive to amoxi-clav or metronidazole. Bacteroides spp. may be resistant to ampicillin and clindamycin [30]. Surgical drainage of abscesses, with aeration and cleansing of infected tissue, is important to resolution. ubcutaneous Nodular Swellings with Ulceration and Draining S Tracts: Nocardia, Rhodococcus and Streptomyces A number of bacterial species, many of which are ubiquitous environmental saprophytes, are rare causes of poorly demarcated nodular swellings with focal ulceration and draining tracts in cats. Infections are often locally invasive, and some species have a propensity to disseminate, particularly in immunocompromised cats. Most infections presumably occur following traumatic implantation. VetBooks.ir 228 L. J. Vogelnest Diagnostic tests are essential to accurately confirm the cause of this presentation. In addition to multiple potential bacteria, differential diagnoses include mycobacteria (Chapter, Mycobacterial Diseases), saprophytic fungi (Chapter, Deep Fungal Diseases) and sterile panniculitis (Chapter, Idiopathic Miscellaneous Diseases). Cytology of FNA from oedematous tissue or fluid pockets or of smears from draining tracts (after initial skin surface cleansing) will typically reveal neutrophils and epithelioid macrophages, sometimes with multinucleate giant cells, regardless of the causal organism. Organisms will more often be detected within macrophages, with morphology varying with the causal species. Histopathology of tissue biopsies will reveal nodular to diffuse pyogranulomatous dermatitis and/or panniculitis. Specials stains help elucidate the likely causal bacteria [38]. Bacterial culture from sterile fluid aspirates or tissue biopsies may be needed to confirm causal species and is optimal to determine antimicrobial susceptibility testing. It is important to alert the laboratory of the potential for unusual bacterial species with special culture requirements. PCR testing can be useful for retrospectively identifying pathogens from formalin- fixed tissue samples if fresh samples are not available for bacterial culture [39]. Nocardiosis Nocardia are ubiquitous soil and decaying vegetation saprophytes that may cause rare but potentially serious infection in cats, typically following implantation into skin wounds. Infection is more common in cats than dogs and may remain localised and indolent or be fulminant with wide dissemination; the latter course is more likely in immunocompromised hosts. N. nova is the most frequently identified causal species, but infections with N. farcinica or N. cyriacigeorgica also occur. Skin infections are most common, with occasional cases restricted to pulmonary or abdominal infection [40]. Clinical Presentation Progressive irregular nodules and punctate draining sinuses are typical (Fig. 11), often with concurrent malaise and respiratory signs. Skin infection may start with discrete abscesses that gradually extend into discharging, non-healing wounds. The extremities, ventral abdomen and inguinal areas are more often affected, and lymphadenopathy is common. Discharge may contain gritty granules (bacterial microcolonies) [40]. Diagnosis Filamentous bacteria that stain at least partially with acid-fast stains are typically prevalent on cytology and histopathology and appear branching or beaded (Fig. 12). Organisms may be found within clear lipid vacuoles [40]. Bacterial culture is slow; it is important to forewarn laboratories with potential cases. Treatment Prompt early treatment of acute lesions, even in immunocompromised patients, can result in good outcomes. Surgical debridement and drainage to reduce residual organisms are optimal, and aggressive early excision, with potential later corrective surgery, is indicated. C&S is important to maximise treatment success. N. nova tends to have less resistance than other species and is often susceptible to sulphonamides, VetBooks.ir Bacterial Diseases 229 Fig. 11 Localised swelling, ulceration and training tract in a cat affected by cutaneous nocardiosis. (Courtesy of Dr. Carolyn O’Brien) Fig. 12 Cytology of nocardiosis: multiple groups of bacteria (grains) and slender and filamentous Nocardia asteroides microorganisms are evident (MGG 1000×). (Courtesy of Dr. Nicola Colombo) tetracyclines (minocycline, doxycycline), clarithromycin and ampicillin/amoxicillin, but paradoxically not to amoxi-clav (clavulanic acid induces β-lactamase production in these species) nor to FQ. Amoxicillin (20 mg/kg twice daily) combined with clarithromycin (62.5–125 mg/cat twice daily) and/or doxycycline (5–10 mg/kg twice daily) is recommended over sulphonamides. Long-term therapy is generally required (3–6 months), and recurrence is common with shorter treatment. N. farcinica is less commonly identified but is often multidrug resistant and highly pathogenic. Initial parenteral therapy with amikacin and/or imipenem combined with trimethoprim-sulphonamides is a consideration [40]. Rhodococcosis Rhodococcus equi is a ubiquitous soil-borne bacterium commonly pathogenic in horses, where it produces a pyogranulomatous pneumonia and enteritis with high mortality in young foals. Infection is also increasingly documented in humans with immunocompromise and is reported in a small number of cats, involving skin (nodules with VetBooks.ir 230 L. J. Vogelnest focal ulceration and draining tracts, most frequently on the extremities), abdominal or thoracic cavities and/or the respiratory tract [41–43]. In one report, a pyogranulomatous skin disease and cellulitis (Fig. 13), different from usual presentations in cats, were described in a 2-year-old female domestic shorthaired cat [43]. Infection in local lymph nodes, presumably via lymphatic spread, is reported [41–43]. Implantation of organisms via skin wounds is proposed, with highest risk in cats with exposure to horses; infected foals shed copious bacteria into the environment via faeces [41]. Diagnosis Cytology of FNA samples and/or histopathology usually readily reveals gram-positive cocci to coccobacilli within macrophages (Fig. 14) [42, 43]. Bacterial culture is essential to confirm a diagnosis; the bacteria grow readily with aerobic culture within 48 hours, but organisms may be protected within macrophages in fluid samples, so tissue samples may be optimal [42]. Treatment C&S is important to guide potential therapy. R. equi infections are often refractory to conventional therapies in horses, and although a combination of rifampicin and erythromycin has been recommended, increasing resistance is recFig. 13 Cutaneous Rhodococcus equi infection in a cat: pyogranulomatous dermatitis and cellulitis with superficial ulceration. (Courtesy of Dr. Anita Patel) Fig. 14 Cytology of case in Figure 13: intracellular Rhodococcus equi organisms are evident in macrophages (MGG 1000×). (Courtesy of Dr. Anita Patel) VetBooks.ir Bacterial Diseases 231 ognised [28]. In a confirmed feline case with a chronic limb lesion, R. equi displayed intermediate sensitivity to amoxi-clav, rifampicin and erythromycin and sensitivity to cephalexin and gentamicin, but the cat deteriorated despite initial cephalexin and later surgical debridement and gentamicin therapy and was euthanised [42]. In another case with sensitivity reported to doxycycline, enrofloxacin and cefuroxime, response to enrofloxacin and later doxycycline was poor [43]. However, doxycycline was reported effective in thee kittens with R. equi pneumonia, from two litters in a cattery in Australia where the source of the infection was undetermined [41]. Streptomycosis Streptomyces spp. are ubiquitous environmental bacteria that very rarely cause irregular nodular lesions with draining tracts and dark tissue granules on the limbs and ventral abdomen of cats. One cat without skin lesions had mesenteric and lymph node infection. Two cats were FIV and/or FeLV positive and two cats had unknown viral status [38]. Diagnosis Gram-positive rods to coccobacilli were present on cytology and histopathology, and bacteria were identified by PCR testing [38]. Treatment All four cats failed to respond to surgical and/or multiple antibiotic therapy and were euthanised following 6–18 months of disease [38]. Dermatophilosis Dermatophilosis is a contagious and potentially zoonotic disease caused by Dermatophilus congolensis, which most commonly affects cattle, sheep and horses in tropical and subtropical climates. The organism does not survive readily in the environment, and infected or carrier animals are the main source. Infection is reported very rarely in cats. Two presumptive cases presented with nodular swelling and draining tracts overlying infected lymph nodes, with associated skin surface crusting. Characteristic gram-positive branching filamentous bacteria were evident on histopathology, and both cats resided on farms in tropical northern Australia. Surgical excision was curative in one cat, and the other cat was euthanised prior to diagnostics [44]. Dermatophilus congolensis was isolated in pure culture from crusts in another cat presenting with crusting and exudation on the ventrolateral lip margins; it was reported sensitive to oxytetracycline and penicillin, but resistant to ampicillin, amoxicillin, gentamicin and cefoperazone [45]. Characteristic filamentous branching bacteria (Fig. 15) were present on cytology from a fourth cat with draining tracts on two lower limbs; bacterial culture was negative, but the cat responded completely to amoxicillin therapy for 10 days [46]. Streptococcal Infection One case of extensive oedematous swelling with multifocal ulceration and draining tracts is reported on the hindlimb of a cat, associated with numerous clusters and chains of gram-positive cocci, identified by tissue PCR as Streptococcus spp., in skin VetBooks.ir 232 L. J. Vogelnest Fig. 15 Cytology of Dermatophilus congolensis: long colonies, like train tracks, are characteristic (Diff Quik, 1000x) and underlying bone. Clusters of bacteria surrounded by eosinophilic amorphous material (Splendore-Hoeppli phenomenon) were present on histopathology [39]. Actinomycosis Actinomyces spp. are oral saprophytes in a variety of animals including dogs and cats, which are most commonly associated with soft tissue and bone infections in the jaws of cattle. Rare cutaneous infections are reported in dogs, characterised by nodular swellings with discharge, typically on the extremities. Although abdominal infection with Actinomyces spp. is documented in one cat, and isolation of Actinomyces spp. is reported concurrently with other bacterial species, or from lesions without concurrent histopathological confirmation, there are no confirmed reports of Actinomyces spp. causing cutaneous infections in cats [47, 48]. apidly Progressive Oedematous Swelling to Necrosis and Septic R Shock: Necrotizing Fasciitis Necrotizing fasciitis is a rapidly progressive and frequently fatal syndrome caused by severe bacterial infection of subcutaneous tissue (fascia) and adjacent skin, typically associated with septic shock. Streptococcus canis is a recognised cause of fulminant disease in humans and dogs and has also been associated with an outbreak of fatal necrotizing fasciitis in shelter cats in southern California. Clonal bacteria were identified and spread via close physical contact was proposed. S. canis is a normal inhabitant of the urinary, reproductive and gastrointestinal tracts of dogs and cats, and although infections are rare and most typically associated with immunocompromise, necrotizing fasciitis can occur in immunocompetent hosts. In contrast to dogs where S. canis is mainly associated with skin infections, respiratory tract infections are more typical in cats [49]. One case associated with S. canis in a single cat following minor limb trauma is also reported [50]. VetBooks.ir Bacterial Diseases 233 Fig. 16 Large areas of necrosis and ulceration in a cat with necrotising fasciitis. (Courtesy of Dr. Susan McMillan) Another form of necrotizing fasciitis in people, occurring after minor skin trauma (catheterisation, hospitalisation), has been associated with multiple concurrent bacteria including Staphylococcus spp., Streptococcus spp., Pseudomonas spp. and E coli. Single case reports in cats are described due to Acinetobacter baumannii [51] and multiple bacteria (E. coli, Enterococcus sp. and S. haemolyticus; E. coli, Enterococcus faecium and S. epidermidis) [52, 53]. Clinical Presentation Poorly demarcated painful regions of oedema and erythema are typical, associated with rapid development of signs of septic shock (pyrexia, severe malaise, collapse). Skin lesions progress to large areas of skin necrosis (Fig. 16). Diagnosis FNA of affected regions reveals neutrophilic inflammation, and causal bacteria are usually apparent intracellularly within neutrophils. Bacterial culture of sterilely collected fluid or tissue samples is required to confirm the causal species. It is important to interpret culture results in conjunction with bacterial morphology from cytology and/ or histopathology, as contaminant species may be cultured from exudative lesions. VetBooks.ir 234 L. J. Vogelnest Treatment Most cases reported in cats have been fatal. Urgent extensive surgical debridement, with removal of the bacterial nidus and all necrotic tissue to limit further extension along fascial planes, is recognised as crucial for suspected cases prior to availability of diagnostic test results, together with broad-spectrum intravenous antimicrobial treatment and critical care. Reconstructive surgery may be required after recovery [50]. Diagnostic Tools for Feline Cutaneous Bacterial Infections Clinical Lesions and Historical Features Prior to reaching for diagnostic tests, careful clinical examination and history taking for each case can focus the diagnostic possibilities and guide the most appropriate test choices. Knowledge of the more likely differentials for specific skin lesions, and the major differentials when bacterial infections are being considered, is helpful (see Table 1). Cytology Cytology is often the most useful initial test when considering bacterial dermatoses and may confirm a diagnosis. The most suitable technique will vary with the clinical lesions (see Table 1). Adhesive tape impressions are suitable for all superficial skin lesions, including alopecia, scaling, crusting, excoriations, ulceration and papules. More exudative lesions can be gently blotted with a dry gauze swab prior to sampling. Good quality adhesive tape (clear, transparent, strongly adhesive; 18–20 mm width) is optimal for use on standard glass slides. Tape strips (~5–6 cm long) are pushed firmly onto lesional skin, squeezing gently on intact papules or plaques and repositioning repeatedly until adhesiveness reduces. Tapes are stained with a Romanowsky stain (e.g. Diff-Quik®) without initial fixation (dissolves the adhesive, reducing clarity). Use of the red stain is useful in cats to aid identification of eosinophils. Tapes can be dipped into stain pots, as for glass slides (Fig. 17). Glass slide impressions are suitable for moist lesions, including erosions and ulcers, and for sampling pustules after rupture with a sterile needle. Slides are stained with a Romanowsky stain including the fixative. Heat fixing is not required. Fine needle aspirates are suitable for deeper lesions, including larger papules and nodules. The skin surface should be gently disinfected with alcohol prior to sampling. Aspirated samples are quickly sprayed from the hub of the needle onto glass slides using an air-filled syringe. Slides are air-dried prior to routine staining with a Romanowsky stain or with gram and/or acid-fast stains for identification of less common bacterial species. Bacterial Diseases b c VetBooks.ir a 235 d e f Fig. 17 Staining of an adhesive tape impression: (a) after sample collection, the tape is pressed firmly at one end, adhesive side down, onto a glass slide and curled into a slightly offset cylinder; (b) tape is dipped into red stain of Diff-Quik® (6 × 1 s dips); (c) tape is dipped into blue stain of Diff-Quik® (6 × 1 s dips); (d) stain is rinsed off tape under a gentle stream of water; (e) tape is uncurled by grasping free edge with forceps and laid flat on the glass slide; (f) tape is dried and flattened firmly onto the glass slide by wiping the surface firmly with a tissue Interpretation of Cytology Samples Bacteria are very sparse in an oil immersion field (OIF: 1000x magnification). Oil immersion is required for accurate recognition of bacteria on normal skin surface samples despite being readily culturable from skin surface swabs (which sample thousands of OIF). The presence of increased numbers of bacteria clustered (colonising) on keratinocytes represents bacterial overgrowth (Fig. 18), while bacteria present intracellularly or closely associated within neutrophils (Figs. 19 and 20) and/or macrophages confirm infection. In deeper samples (e.g. FNA), bacteria should be absent if VetBooks.ir 236 L. J. Vogelnest Fig. 18 Numerous cocci clustered on keratinocytes on an adhesive tape impression confirm bacterial overgrowth, while cocci intracellularly within one intact neutrophil (multi-lobed nucleus) suggest concurrent focal bacterial infection (100x lens, oil immersion; stained with Diff-Quik® as per Fig. 17) Fig. 19 Cocci intracellularly and associated with degenerate neutrophil remnants and nuclear streaming on an adhesive tape impression confirm bacterial infection (100x lens, oil immersion; stained with Diff-Quik® as per Fig. 17) sterile technique was successfully employed; the presence of any bacteria is abnormal. Adhesive tape impressions require some experience for efficient and accurate examination. Keratinocytes typically dominate, staining pale to midblue and ranging from sheets of flat polyhedral cells to single or clustered shards (follicular cells). Inflammatory cells stain purple, with neutrophils most prevalent; they may be in small clusters or form peripheral rims around keratinocyte sheets. Eosinophils may also be present, particularly in cases with underlying hypersensitivity. Neutrophils should be plentiful in erosive or ulcerative samples but may be relatively sparse in drier lesions. Neutrophils degenerate quickly on the skin surface, often appearing as elongated strands of nuclear material (nuclear streaming). Tapes should be scanned under low power microscopy (4x lens) for areas of dense cells or neutrophil clusters to e xamine under higher power (see Fig. 20). Microscope oil is placed directly on the tape surface to examine under OIF. VetBooks.ir Bacterial Diseases 237 Fig. 20 Keratinocytes distributed singly and in sheets on an adhesive tape impression with a central neutrophil cluster (4x lens; stained with Diff-Quik® as per Fig. 17) Bacterial Culture Culture and antibiotic susceptibility testing (C&S) is vital for bacterial infections caused by species with unpredictable antimicrobial sensitivity profiles, such as rods and many of the environmental bacteria that cause sporadic deep infections. In contrast, empirical therapy based on cytology is considered appropriate for many cases of SBP [22]. C&S is indicated in severe life-threatening infections, if rod-shaped bacteria are evident on cytology (where sensitivity is less predictable), if empirical therapy does not resolve lesions or when antibiotic resistance is more likely in that geographical region or patient [1, 22]. There is no current evidence to support any negative influence of current antibiotic therapy on isolation of causative bacteria; thus, withdrawal of systemic or topical antibiotics is considered unnecessary [23]. Superficial Skin Sampling Collection of culture samples from primary lesions is optimal with pustules ruptured and papules incised with a needle prior to sampling with a culture swab, without preceding skin disinfection [22, 23]. Sterile tissue biopsy may be more reliable for papules [23]. In dogs with SBP, dry culture swabs were equally effective as moistened swabs or light scrapings for sampling a range of superficial lesions, including papules. Swabs were rubbed vigorously for 5–10 seconds on representative lesions, confirmed as SBP on cytology, without prior skin disinfection [54]. Culture swabs from the skin surface have also been well utilised for numerous feline skin culture studies sampling a range of skin lesions [5, 7, 9, 17, 19]. Swabs should be immediately placed in transport medium and VetBooks.ir 238 L. J. Vogelnest o ptimally refrigerated prior to transit to limit overgrowth of contaminants, particularly in warm climates. Multiple strains of S. pseudintermedius, with distinct antimicrobial resistance profiles, have recently been detected from single lesions in canine SBP, with pustules and, to a lesser extent, papules associated with less species and strain diversity than collarettes and crusts. Pustules and papules were swabbed after incision with the tip of a sterile needle. Crusts and collarettes were sampled by touching a culture swab to the edges of lesions [55]. These findings reinforce the value of sampling primary lesions whenever possible and raise the potential importance of collecting multiple samples from a range of primary lesions to aid identification of all potential pathogens collectively contributing to infection in a patient. Deeper Skin Sampling FNA or tissue biopsies collected with sterile technique are appropriate for bacterial culture from nodular lesions, with tissue samples most reliable. The surface epidermis may be excised after sample collection to help avoid isolation of contaminants. Swabs of discharging tracts are not suitable, as a range of contaminant bacteria are readily isolated [22]. When an infectious cause remains uncertain, and a range of infectious agents with varying culture requirements are differentials, tissue culture samples can be held refrigerated in a sterile container on a sterile saline-moistened swab, pending histopathology. Culture Techniques Minimum microbiology evaluation should include complete speciation of staphylococci, regardless of tube coagulase status, and an antibiogram for all cultured isolates [1]. In-house culturing can be clinically misleading, resulting in erroneous and ineffective treatments and is not recommended, particularly for superficial skin sampling [28]. Culture Interpretation Culture results should always be interpreted in light of concurrent cytology findings and the likely pathogens in that location. Growth of bacteria in the laboratory alone does not confirm a pathogenic role. The morphology of cultured isolates must be consistent with morphology of bacteria evident on cytology for isolates to be relevant. Even bacteria with alarming multidrug resistance profiles can be inadvertent contaminants or incidental commensals, without any role in the current skin disease [1, 22]. However, correctly discerning the relevance of cultured isolates is not always straightforward; although CoPS are proposed as the major skin pathogens, commensal CoNS and a variety of environmental saprophytes may be pathogenic at times, particularly with concurrent immunosuppression [1, 22]. Histopathology Skin biopsies for histopathology are essential to confirm a diagnosis for many deep nodular lesions. Multiple excisional biopsies are optimal, sampling any smaller VetBooks.ir Bacterial Diseases 239 peripheral lesions in addition to large lesions and avoiding central areas of large lesions which may be necrotic. Larger lesions should be sectioned to ensure adequate formalin penetration. Biopsies for histopathology should be placed in formalin immediately after collection. Biopsy samples can also be retained frozen for potential PCR or other molecular testing. Histopathology is less often indicated for superficial infections but may be important where cytology results are inconclusive or presentations are atypical for SBP. Punch biopsies are suitable for small lesions (pustules, papules) or uniform lesions (plaques, erythema, crusting). Elliptical samples are most useful for transitional areas and edges of ulcerative lesions. PCR Testing PCR testing can be helpful to identify species not readily culturable in the laboratory. It is ideally performed on fresh tissue biopsies, collected with sterile technique, but can also be performed on formalin-fixed samples, assuming fixation in formalin was for <24 hour. PCR detection from swab samples does not confirm any role as a pathogen for environmental bacteria (e.g. Nocardia spp.) as detection may simply reflect skin contaminants. reatment Principles for Feline Cutaneous Bacterial Infections T and Antimicrobial Stewardship Antimicrobial Resistance and Stewardship Increasing development of antimicrobial resistance is of profound concern in recent years and has marked impact on human and animal health and related economics. It is undeniable that antimicrobial use can result in antimicrobial resistance in the species that is being treated and that some resistant pathogens or resistance mechanisms can be transmitted bi-directionally between animals and humans [1, 28, 56]. Methicillin resistance of Staphylococcus spp. relevant to veterinary medicine has been recognised as a serious problem worldwide since the late 1990s, with geographical variation in incidence, but rapid escalation of resistant S. pseudintermedius (MRSP), S. aureus (MRSA) and S. schleiferi species. Acquisition of methicillin resistance confers resistance to all β-lactam antibiotics, including cephalosporins. MRS isolates also frequently acquire co-resistance to other classes of antibiotics, especially FQ and macrolides [18, 19]. MRSP in particular is not uncommonly multidrug resistant (resistance to at least six antibiotic classes). As S. pseudintermedius is a major canine pathogen and a recognised feline pathogen, this has created significant new veterinary challenges [1]. Inappropriate use of antibiotics in the veterinary arena is considered an important factor promoting progression of resistance [1, 28, 56]. VetBooks.ir 240 L. J. Vogelnest • Cefovecin: Despite being reported as the most frequently chosen antibiotic for use in cats in recent studies, and specifically the most frequently used for skin infections or abscesses, it is a third-generation cephalosporin, which is considered ‘highest priority/critically important antimicrobials’ in human medicine, reserved for life-threatening infections or when culture and susceptibility testing does not indicate alternate antibiotic choices [26, 31]. Reported use is often ‘just in case’, without any clinical and/or cytological evidence to confirm a role for bacterial infection [31]. Alarmingly, only 0.4% of prescriptions in >1000 cats had C&S testing performed at the time of use and none prior to use. In addition, nearly 23% had concurrent glucocorticoid treatment, with long-acting methyl-prednisolone acetate injections in 38% of these, although these drugs are contraindicated in the face of active infections [31]. Prescription of cefovecin due to convenience of administration is not a justification for valid use. • Fluoroquinolones: There is evidence that FQ therapy can promote colonisation with bacteria carrying more resistance genes. FQ therapy was a significant risk factor for isolation of MRS, multidrug-resistant staphylococci, and FQ-resistant staphylococci from mucosal samples in dogs in a recent study in England [56]. Clindamycin and amoxi-clav therapy were not significantly associated with detection of antibiotic resistance, but cephalexin was, potentially due to longer treatment courses typically used in contrast to amoxi-clav. FQ maintained this effect at 1 month post-treatment and cephalexin until at least 3 months post- treatment [56]. FQ should not be used as first-line treatment options. Feline MRS Infections There are increasing reports of MRSP and MRSA skin isolates from cats with skin lesions, although rarely with confirmed pyoderma, in multiple regions of the world [6, 8, 10, 57]. Variable co-resistance of isolates is documented, including MRSA with FQ resistance (11.8%) in Australia [10], MRSP with multidrug resistance in Thailand [57] and MRSP also resistant to TMS (30.8%), chloramphenicol (7.7%) or clindamycin (7.7%) in Australia [10]. MRSP isolates from cats are typically sensitive to rifampicin, FQ (second- or third-generation) and amikacin. CoNS that are more frequently isolated in cats are also often methicillin- resistant and multidrug resistant [6]. Risk factors increasing the likelihood of MRS infections in cats are currently unknown. Risk factors identified in dogs include prior antibiotic therapy, eating animal stools and contact with veterinary hospitals. Despite confirmed sharing of staphylococcal isolates including MRSP between pets, dogs from multidog households appear less likely to have mucosal MRS [56]. Antimicrobial Stewardship The appropriate use of antimicrobials to reduce promotion of further antimicrobial resistance is an important concept referred to as antimicrobial stewardship. The first important principle of appropriate antibiotic usage is to prescribe antibiotics only in patients with sufficient evidence to confirm a diagnosis of bacterial infection. Use of antibiotics ‘just in case’, especially without prior diagnostics or when diagnostics fail to confirm bacterial infection, is strongly discouraged [23, 24, 26, 30, 31]. VetBooks.ir Bacterial Diseases 241 The second important principle of appropriate antibiotic usage is wise choice of antibiotic, based on the likely causal bacteria and their likely sensitivity profiles. Empirical choice is appropriate for diseases where causal pathogens are fairly predictable and have fairly predictable antibiotic susceptibility profiles and first-line antibiotics (see later) are appropriate. Use of antibiotics that have greater value for some resistant bacteria (second- or third-line antibiotics) is not suitable without evidence from C&S that they are appropriate and first-line choices are not, unless facing life-threatening situations. The final important principle of appropriate antibiotic usage is to use the correct dose and duration of the chosen antibiotic, taking care to weigh patients accurately prior to therapy and rounding doses up rather than under-dosing (see Table 2). Although sound evidence is lacking, it is generally recommended that treatment of superficial infections continues for 3 weeks and deep infections for at least 4 weeks (and sometimes many months for difficult pathogens). See specific diseases for further guidelines. Antibiotic Choices Antibiotic classes are divided into generations based on differences in their spectrum of activity [30], and they can also be divided into groups based on current prescribing guidelines. There is no clear consensus on optimal antibiotic choices for bacterial infections in either dogs or cats [1, 26, 28, 30, 31, 58], with a general paucity of scientific evidence to clarify. The following recommendations for feline cutaneous bacterial infections are based on a compilation of current expert opinion in both veterinary and human medicine. First-line antibiotics are considered most appropriate for empirical therapy of diagnosed infections, as they are generally well-tolerated and have high efficacy against the expected causal bacteria [26]. Empirical therapy appears suitable for treatment of feline pyoderma. First-line choices for feline pyoderma are the following: • Amoxi-clav or cephalexin – both reported with high levels of sensitivity to isolated Staphylococcus spp. [8] Even in regions where MRS are common in canine SBP, MRS infections in cats appear very rare, and most reports are of laboratory isolates [18, 19]. Second-line antibiotics should only be used when there is culture evidence that first-line drugs will not be effective or as initial empirical therapy for severe infections while awaiting C&S results if resistance to first-line drugs is more likely. This classification includes newer broad-spectrum antibiotics important to animal and human health, so reserving their use to necessary cases is prudent. Not all second- line choices are equal, with a hierarchical consideration recommended, guided by regional data [30]. Second-line antibiotics relevant to treatment of feline skin infections include the following: AMC (20 – 25 BID) S b,c Sb M CX (20– DXY a (5 BID) 25 BID) A (DBP only) S METR (10 BID) GIT (mild) GIT (more) Oesophageal stricture (water-swallow) GIT (mild) Sd Retinal degeneration (enro, higher doses) R R Myelosuppression; aplastic anaemia in people handling Some MSSP/MSSA Some MRSP/MRSA Blood dyscrasia M Second-line: only when C&S supports use and first-line not suitable; or while C&S pending if resistance likely (dose mg/kg, frequency) FQ 2nd Marbo CHL (50 BID) TMS (15 CLI BID) (5.5– (2.7–5.5 SID), 11 Enro BID) (5 SID) MSSP/ MSSA only Retinal degeneration (orbi, higher doses) R Some MRSP/ MRSA Severe risk: renal, hepatic, ototoxic M MRSP/ MRSA Third-line:only when C&S supports use and no other choices (dose mg/kg, frequency) GNT, CFV e FQ 3 rd Prado (8 q (7.5 SID) Orbi AMK, RIF 14d) (2.5–7.5 SID) Critical: (no veterinary use) VAN, TEI, TEL, LIN ∗ Some regional variation acceptable: judicious antibiotic use requires consideration of local availability, veterinary licensing, recommendations for human use, and regional antimicrobial susceptibility data [1] Antibiotic abbreviations: AMC amoxicillin-clavulanic acid, AMK amikacin, CFV cefovecin, CHL chloramphenicol, CLI clindamycin, CX cephalexin, cefadroxil; d day, DXY doxycycline, Enro enrofloxacin, FQ 2nd second generation fluoroquinolone, FQ 3rd third generation fluoroquinolone, GNT gentamicin, LIN linezolid, Marbo marbofloxacin, Orbi orbifloxacin, Prado pradofloxacin, q every, RIF rifampicin, TEI teicoplanin, TEL telavancin, TMS trimethoprim sulphonamide, VAN vancomycin Side effects Abscess S M M /cellulitis Nocardia R R M R Rhodococcus R R M R No antibiotics “Just in case” use strongly Uncertain discouraged[24,56] SBP/ DBP Diagnosis First-line: potential empirical therapy (dose mg/kg, frequency) Table 2 Systemic antibiotic choices for feline bacterial infections in line with antimicrobial stewardship guidelines∗ [26, 28, 30, 31, 58] VetBooks.ir 242 L. J. Vogelnest General abbreviations: A potential adjunctive value only: not as sole treatment, C&S culture and antibiotic susceptibility testing, DBP deep bacterial pyoderma, GIT gastro-intestinal tract, M some resistant isolates, at least in some geographical regions, MSSP methicillin-sensitive Staphylococcus pseudintermedius, MRSP methicillin-resistant Staphylococcus pseudintermedius, MSSA methicillin-sensitive Staphylococcus aureus, MRSA methicillin-resistant Staphylococcus aureus, MSSA methicillin-sensitive Staphylococcus aureus, R high levels of resistance for common causal bacteria, S typically high levels of sensitivity for causal bacteria, SBP superficial bacterial pyoderma a May be best considered 2nd-line, particularly in regions where MRSP-isolates are more often susceptible to doxycycline; Minocyclin 8mg/kg once daily can be used if doxycycline unavailable/expensive b Assuming intracellular cocci are present on cytology c May be the choice when cocci and rods are present on cytology; C&S is indicated if rods are exclusively present on cytology d Resistance occurs with some Bacteroides spp,. and most gram-negative bacteria e Often considered second-line, or even first-line; however, third-generation cephalosporins are considered third-line in human medicine VetBooks.ir Bacterial Diseases 243 VetBooks.ir 244 L. J. Vogelnest • Clindamycin – registered for use in many countries for skin and soft-tissue infections. Although there is some debate in veterinary medicine, macrolide antibiotics are not first-line choices in human medicine [30]. Clindamycin has also been shown to have lower levels of sensitivity to staphylococcal isolates in some studies, and a bacterial culture and susceptibility test is recommended prior to its use [8]. • Doxycycline – considered first-line in some regions. However, it may be generally less suitable as a first-line choice considering that high levels of resistance are documented in staphylococcal isolates in some regions [10, 29], even though lower resistance in others [8]. Minocycline has a similar spectrum of action to doxycycline and is less expensive and more available in some countries but may be associated with more gastrointestinal irritation [30]. • Cefovecin – effective against some gram-negative and anaerobic bacteria in addition to gram-positive bacteria, providing a broader spectrum of activity than second-generation cephalosporins such as cephalexin. There is generally poor activity against Pseudomonas spp. and enterococci. Although typically considered first- or second-line in veterinary medicine, third-generation cephalosporins are considered critically important antibiotics in human medicine reserved for life-threatening diseases (third-line), so classification as second-line is questioned [30]. • Second-generation FQ (enrofloxacin, difloxacin, marbofloxacin, ciprofloxacin) – primarily target gram-negative bacteria, which are less frequent skin pathogens. • Trimethoprim-sulphonamides – greater risk of side effects in cats and lower sensitivity of many bacteria compared to other choices reduce the suitability of this option; may be effective for some MRS. Third-line antibiotics are very important to animal and human health, especially for treatment of multidrug-resistant bacteria, and their use should be only considered when C&S indicates a lack of other treatment choices. Many are not licensed for veterinary use [26, 30]. Their use for superficial infections is strongly discouraged. Third-line choices for cats with severe bacterial cutaneous infections include the following: • Third-generation FQ (pradofloxacin and orbifloxacin) – have an increased gram-positive and anaerobic spectrum compared to second-generation FQ, in addition to good gram-negative coverage; considered unlikely to be effective for Nocardia spp. [30]. • Aminoglycosides (gentamicin, amikacin) – potential considerations only for life- threatening skin infections, but have considerable risk of severe renal side effects, requiring careful monitoring, concurrent fluid therapy and brief duration therapy VetBooks.ir Bacterial Diseases 245 • Other new and old antibiotics (chloramphenicol, clarithromycin, rifampicin, imipenem, piperacillin) – potential use for MRS and multidrug-resistant bacteria, but considerable potential for moderate to severe side effects • Newest generation antibiotics (e.g. vancomycin, teicoplanin, telavancin, linezolid) – deemed of critical importance to human health and strongly discouraged/unavailable for veterinary use [1, 26] Management of Veterinary Patients with MRS Infection Transmission of MRS between humans and various animal species including cats is documented [1, 28]. MRSA and methicillin-resistant CoNS, including S. haemolyticus, S. epidermidis and S. fleurettii, were co-isolated from multiple cats, horses and humans on one farm in Europe, with isolates sharing the same characteristics [59]. Concern is thus raised when MRS infections are documented in veterinary species, when greater bacterial numbers are likely to increase the risks of transmission. It is currently recommended that pets with MRS infections have limited contact with other pets or humans until their infections are controlled and that good hand hygiene and heightened cleaning protocols are used in the home environment to reduce potential transmission. Veterinary hospitals are also recognised as potential sources of MRS transmission, and adherence to strict hand hygiene (proper washing/drying and use of alcohol-based hand sanitizers) between handling all patients and regular cleaning and disinfection protocols will reduce the risks of transmission, with MRS susceptible to commonly used disinfectants. Barrier nursing protocols for hospitalised patients with known MRS infections are recommended [1, 56]. Despite concerns over the potential challenges of treatment of MRS infection, resistant isolates are not more virulent or likely to cause infection than non-resistant isolates. There is no current evidence to support attempted decolonisation of patients colonised by MRS, and thus, screening of clinically normal animals for carriage of MRS is currently not recommended [1]. Conclusion Feline cutaneous bacterial infections range from common secondary to rare but potentially life-threatening deep and disseminated infections. Causal pathogens include normal skin and mucosal commensals and a range of environmental saprophytes. Development of antimicrobial resistance, particularly methicillin resistance in staphylococci, poses increasing veterinary challenges. Accurate and efficient VetBooks.ir 246 L. J. Vogelnest diagnosis is important to expedite appropriate treatment and to limit further promotion of antibiotic resistance by restricting use of antibiotics to patients with confirmed disease. References 1. Morris DO, Loeffler A, Davis MF, Guardabassi L, Weese JS. Recommendations for approaches to methicillin-resistant staphylococcal infections of small animals: diagnosis, therapeutic considerations and preventative measures: Clinical Consensus Guidelines of the World Association for Veterinary Dermatology. Vet Dermatol. 2017;28:304–30. 2. Rossi CC, da Silva DI, Mansur Muniz I, Lilenbaum W, Giambiagi-deMarval M. The oral microbiota of domestic cats harbors a wide variety of Staphylococcus species with zoonotic potential. Vet Microbiol. 2017;201:136–40. 3. Weese JS. The canine and feline skin microbiome in health and disease. Vet Dermatol. 2013;24:137–45. 4. Patel A, Lloyd DH, Lamport AI. Antimicrobial resistance of feline staphylococci in South- Eastern England. Vet Dermatol. 1999;10:257–61. 5. Patel A, Lloyd DH, Howell SA, Noble WC. Investigation into the potential pathogenicity of Staphylococcus felis in a cat. Vet Rec. 2002;150:668–9. 6. Muniz IM, Penna B, Lilenbaum W. Methicillin-resistant commensal staphylococci in the oral cavity of healthy cats: a reservoir of methicillin resistance. Vet Rec. 2013;173:502.2. https:// doi.org/10.1136/vr.101971. 7. Igimi SI, Atobe H, Tohya Y, Inoue A, Takahashi E, Knoishi S. Characterization of the most frequently encountered Staphylococcus sp. in cats. Vet Microbiol. 1994;39:255–60. 8. Qekwana DN, Sebola D, Oguttu JW, Odoi A. Antimicrobial resistance patterns of Staphylococcus species isolated from cats presented at a veterinary academic hospital in South Africa. BMC Vet Res. 2017;13:286. https://doi.org/10.1186/s12917-017-1204-3. 9. Abraham JK, Morris DO, Griffeth GC, Shofer FS, Rankin SC. Surveillance of healthy cats and cats with inflammatory skin disease for colonization of the skin by methicillin-resistant coagulase-positive staphylococci and Staphylococcus schleiferi ssp. schleiferi. Vet Dermatol. 2007;18:252–9. 10. Saputra S, Jordan D, Worthing KA, Norris JM, Wong HS, Abraham R, et al. Antimicrobial resistance in coagulase-positive staphylococci isolated from companion animals in Australia: a one year study. PLoS One. 2017;12:e0176379. https://doi.org/10.1371/0176379. 11. Older CE, Diesel A, Patterson AP, Meason-Smith C, Johnson TJ, Mansell J, Suchodolski J, Hoffmann AR. The feline skin microbiota: the bacteria inhabiting the skin of healthy and allergic cats. PLoS One. 2017;12:e0178555. https://doi.org/10.1371/vr.0178555. 12. Wildermuth BE, Griffin CE, Rosenkrantz WS. Feline pyoderma therapy. Clin Tech Small Anim Pract. 2006;21:150–6. 13. Scott DW, Miller WH, Erb HN. Feline dermatology at Cornell University: 1407 cases (1988– 2003). J Fel Med Surg. 2013;15:307–16. 14. Yu HW, Vogelnest LJ. Feline superficial pyoderma: a retrospective study of 52 cases (2001– 2011). Vet Dermatol. 2012;23:448–55. 15. Whyte A, Gracia A, Bonastre C, Tejedor MT, Whyte J, Monteagudo LV, Simon C. Oral disease and microbiota in free-roaming cats. Top Companion Anim Med. 2017;32:91–5. 16. Wooley KL, Kelly RF, Fazakerley J, Williams NJ, Nuttal TJ, McEwan NA. Reduced in vitro adherence of Staphylococcus spp. to feline corneocytes compared to canine and human corneocytes. Vet Dermatol. 2006;19:1–6. 17. Medleau L, Blue JL. Frequency and antimicrobial susceptibility of Staphylococcus spp isolated from feline skin lesions. J Am Vet Med Assoc. 1988;193:1080–1. VetBooks.ir Bacterial Diseases 247 18. Morris DO, Rook KA, Shofer FS, Rankin SC. Screening of Staphylococcus aureus, Staphylococcus intermedius, and Staphylococcus schleiferi isolates obtained from small companion animals for antimicrobial resistance: a retrospective review of 749 isolates (2003–04). Vet Dermatol. 2006;17:332–7. 19. Morris DO, Maudlin EA, O’Shea K, Shofer FS, Rankin SC. Clinical, microbiological, and molecular characterization of methicillin-resistant Staphylococcus aureus infections of cats. Am J Vet Res. 2006;67:1421–5. 20. Selvaraj P, Senthil KK. Feline Pyoderma – a study of microbial population and its antibiogram. Intas Polivet. 2013;14(11):405–6. 21. White SD. Pyoderma in five cats. J Am Anim Hosp Assoc. 1991;27:141–6. 22. Beco L, Guaguere E, Lorente Mendez C, Noli C, Nuttall T, Vroom M. Suggested guidelines for using systemic antimicrobials in bacterial skin infections (1): diagnosis based on clinical presentation, cytology and culture. Vet Rec. 2013;172:72–8. 23. Hillier A, Lloyd DH, Weese JS, Blondeau JM, Boothe D, Breitschwerdt E, et al. Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Vet Dermatol. 2014;25:163–74. 24. Singleton DA, Sanchez-Vizcaino F, Dawson S, Jones PH, Noble PJ, Pinchbeck GL, et al. Patterns of antimicrobial agent prescription in a sentinel population of canine and feline veterinary practices in the United Kingdom. The Vet J. 2017;224:18–24. 25. Wildermuth BE, Griffin CE, Rosenkrantz WS. Response of feline eosinophilic plaques and lip ulcers to amoxicillin trihydrate–clavulanate potassium therapy: a randomized, double-blind placebo-controlled prospective study. Vet Dermatol. 2011;23:110–8. 26. Beco L, Guaguere E, Lorente Mendez C, Noli C, Nuttall T, Vroom M. Suggested guidelines for using systemic antimicrobials in bacterial skin infections (2): antimicrobial choice, treatment regimens and compliance. Vet Rec. 2013;172:156–60. 27. Borio S, Colombo S, La Rosa G, De Lucia M, Dombord P, Guardabassi L. Effectiveness of a combined (4% chlorhexidine digluconate shampoo and solution) protocol in MRS and non- MRS canine superficial pyoderma: a randomized, blinded, antibiotic-controlled study. Vet Dermatol. 2015;26:339–44. 28. Weese JS, Giguere S, Guardabassi L, Morley PS, Papich M, Ricciuto DR, et al. ACVIM consensus statement on therapeutic antimicrobial use in animals and antimicrobial resistance. J Vet Intern Med. 2015;29:487–98. 29. Mohamed MA, Abdul-Aziz S, Dhaliwal GK, Bejo SK, Goni MD, Bitrus AA, et al. Antibiotic resistance profiles of Staphylococcus pseudintermedius isolated from dogs and cats. Malays J Microbiol. 2017;13:180–6. 30. Whitehouse W, Viviano K. Update in feline therapeutics: clinical use of 10 emerging therapies. J Feline Med Surg. 2015;17:220–34. 31. Burke S, Black V, Sanchez-Vizcaino F, Radford A, Hibbert A, Tasker S. Use of cefovecin in a UK population of cats attending first-opinion practices as recorded in electronic health records. J Feline Med Surg. 2017;19:687–92. 32. Hardefeldt LY, Holloway S, Trott DJ, Shipstone M, Barrs VR, Malik R, et al. Antimicrobial prescribing in dogs and cats in Australia: results of the Australasian Infectious Disease Advisory Panel Survey. J Vet Intern Med. 2017;31:1100–7. 33. Scott DW, Miller WH. Feline acne: a retrospective study of 74 cases (1988–2003). Jpn J Vet Dermatol. 2010;16:203–9. 34. Jazic E, Coyner KS, Loeffler DG, Lewis TP. An evaluation of the clinical, cytological, infectious and histopathological features of feline acne. Vet Dermatol. 2006;17:134–40. 35. Walton DK, Scott DW, Manning TO. Cutaneous bacterial granuloma (botryomycosis) in a dog and cat. J Am Anim Hosp Assoc. 1983;183(19):537–41. 36. Murai T, Yasuno K, Shirota K. Bacterial pseudomycetoma (Botryomycosis) in an FIV-positive cat. Jap J Vet Dermatol. 2010;16:61–5. VetBooks.ir 248 L. J. Vogelnest 37. Norris JM, Love DN. The isolation and enumeration of three feline oral Porphyromonas species from subcutaneous abscessed in cats. Vet Microbiol. 1999;65:115–22. 38. Traslavina RP, Reilly CM, Vasireddy R, Samitz EM, Stepnik CT, Outerbridge C, et al. Laser capture microdissection of feline Streptomyces spp pyogranulomatous dermatitis and cellulitis. Vet Pathol. 2015;205(52):1172–5. 39. De Araujo FS, Braga JF, Moreira MV, Silva VC, Souza EF, Pereira LC, et al. Splendore- Hoeppli phenomenon in a cat with osteomyelitis caused by Streptococcus species. J Feline Med Surg. 2014;16:189–93. 40. Malik R, Krockenberger MB, O’Brien CR, White JD, Foster D, Tisdall PL, et al. Nocardia infections in cats: a retrospective multi-institutional study of 17 cases. Aust Vet J. 2006;84: 235–45. 41. Gunew MN. Rhodococcus equi infection in cats. Aust Vet Practit. 2002;32:2–5. 42. Farias MR, Takai S, Ribeiro MG, Fabris VE, Franco SR. Cutaneous pyogranuloma in a cat caused by virulent Rhodococcus equi containing an 87 kb type I plasmid. Aust Vet J. 2007;85:29–31. 43. Patel A. Pyogranulomatous skin disease and cellulitis in a cat caused by Rhodococcus equi. J Small Anim Pract. 2002;43:129–32. 44. Miller RI, Ladds PW, Mudie A, Hayes DP, Trueman KF. Probable dermatophilosis in 2 cats. Aust Vet J. 1983;60:155–6. 45. Kaya O, Kirkan S, Unal B. Isolation of Dermatophilus congolensis from a cat. J Veterinary Med Ser B. 2000;47:155–7. 46. Carakostas MC. Subcutaneous dermatophilosis in a cat. J Am Vet Med Assoc. 1984;185:675–6. 47. Sharman MJ, Goh CS, Kuipers RG, Hodgson JL. Intra-abdominal actinomycetoma in a cat. J Feline Med Surg. 2009;11:701–5. 48. Koenhemsi L, Sigirci BD, Bayrakal A, Metiner K, Gonul R, Ozgur NY. Actinomyces viscosus isolation from the skin of a cat. Isr J Vet Med. 2014;69:239–42. 49. Kruger EF, Byrne BA, Pesavento P, Hurley KF, Lindsay LL, Sykes JE. Relationship between clinical manifestations and pulsed-field gel profiles of Streptococcus canis isolates from dogs and cats. Vet Microbiol. 2010;146:167–71. 50. Nolff MC, Meyer-Lindenberg A. Necrotising fasciitis in a domestic shorthair cat – negative pressure wound therapy assisted debridement and reconstruction. J Small Anim Pract. 2015;56:281–4. 51. Brachelente C, Wiener D, Malik Y, Huessy D. A case of necrotizing fasciitis with septic shock in a cat caused by Acinetobacter baumannii. Vet Dermatol. 2007;18:432–8. 52. Plavec T, Zdovc I, Juntes P, Svara T, Ambrozic-Avgustin I, Suhadolc-Scholten S. Necrotising fasciitis, a potential threat following conservative treatment of a leucopenic cat: a case report. Vet Med (Praha). 2015;8:460–7. 53. Berube DE, Whelan MF, Tater KC, Bracker KE. Fournier’s gangrene in a cat. J Vet Emerg Crit Care. 2010;20:148–4. 54. Ravens PA, Vogelnest LJ, Ewen E, Bosward KL, Norris JM. Canine superficial bacterial pyoderma: evaluation of skin surface sampling methods and antimicrobial susceptibility of causal Staphylococcus isolates. Aust Vet J. 2014;92:149–55. 55. Larsen RF, Boysen L, Jessen LR, Guardabassi L, Damborg P. Diversity of Staphylococcus pseudintermedius in carriage sites and skin lesions of dogs with superficial bacterial folliculitis: potential implications for diagnostic testing and therapy. Vet Dermatol. 2018;29:291–5. 56. Schmidt VM, Pinchbeck G, Nuttall T, Shaw S, McIntyre KM, McEwan N, et al. Impact of systemic antimicrobial therapy on mucosal staphylococci in a population of dogs in Northwest England. Vet Dermatol. 2018;29:192–202. 57. Kadlec K, WeiB S, Wendlandt S, Schwarz S, Tonpitak W. Characterization of canine and feline methicillin-resistant Staphylococcus pseudintermedius (MRSP) from Thailand. Vet Microbiol. 2016;194:93–7. VetBooks.ir Bacterial Diseases 249 58. Lappin MR, Bondeau J, Boothe D, Breitschwerdt FB, Guardabassi L, Lloyd DH, et al. Antimicrobial use Guidelines for Treatment of Respiratory Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases. J Vet Intern Med. 2017;31:279–94. 59. Loncaric I, Kunzel F, Klang A, Wagner R, Licka T, Grunert T, et al. Carriage of methicillin- resistant staphylococci between humans and animals on a small farm. Vet Dermatol. 2016;27:191–4. VetBooks.ir Mycobacterial Diseases Carolyn O’Brien Abstract Cats may be infected with a variety of both rapidly- and slowly-growing mycobacterial species, which cause a variety of clinical syndromes in cats, from localized skin disease to disseminated and potentially fatal infections. Cutaneous disease is the most common manifestation for all causative species; however, some species may have internal involvement, with any organ system, skeletal or soft tissue structure potentially infected. Infections by rapidly-growing mycobacteria generally result in fistulating panniculitis of the inguinal region or less commonly, axillae, flanks or dorsum, whereas those caused by members of the slow-growing taxons typically present with solitary or multiple nodular skin lesions and/or local lymphadenopathy, especially of the head, neck and/or limbs. Most affected cats do not appear to have an underlying immunosuppressive condition, and no association has been made with a positive retroviral status. Most cases occur in adult cats with unrestricted outdoor access. Depending on the causative species and the extent of disease when first diagnosed, these infections can be challenging to treat. Generally, localized cutaneous infection caused by all species has a relatively favorable prognosis if treated with an appropriate combination of drugs and surgery, if necessary. If the cat acquires systemic infection, the prognosis becomes significantly worse. The commitment of the owner to the implementation of a potentially expensive and time-consuming schedule of multidrug therapy for many months may also influence the outcome. The zoonotic potential of these organisms is generally low, however cat-to-human transfer of Mycobacterium bovis has been reported. C. O’Brien (*) Melbourne Cat Vets, Fitzroy, Victoria, Australia e-mail: cob@catvet.net.au © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_12 251 VetBooks.ir 252 C. O’Brien Mycobacteria are aerobic, nonmotile, Gram-positive, nonspore-forming bacilli in the phylum Actinobacteria. Of the more than 180 mycobacterial species identified [1], almost all are environmental saprophytes. However, a few, such as the Mycobacterium tuberculosis complex (MTB), M. leprae and its relatives, members of the M. avium complex (MAC), such as M. avium subsp. paratuberculosis and M. lepraemurium, appear to have evolved into obligate pathogens. Mycobacterial species can be divided genetically and phenotypically into two main groups: rapidly growing (RGM) and slowly growing mycobacteria (SGM). The RGM are ancestral to the SGM, with the latter forming a distinct genetic subbranch based on analysis of housekeeping genes and, more recently, whole-genome analysis [2]. The M. abscessus/chelonae complex appears to be the genetically oldest group identified, with M. triviale and also the closely related M. terrae group the likely evolutionary links between the RGM and the SGM [2]. Mycobacterial infections cause a variety of clinical syndromes in cats, from minor localized skin disease to potentially fatal disseminated infections. Cutaneous disease is the most common manifestation for all causative species; however, some species, particularly the MTB and MAC, may have internal involvement with any organ system, skeletal or soft tissue structure, potentially infected. Few investigations have examined substantial cohorts of cats with mycobacteriosis and only some definitively identified the causative mycobacterial species via genetic analysis. These studies are typically limited to animals from a particular geographical region and may not be representative of the disease in cats domiciled elsewhere, especially with regard to incidence and causative species. Typically, cats with mycobacterial infections do not appear to have an immunosuppression, and no association has been made with a positive retroviral status, unlike MAC infections in people with human immunodeficiency virus/acquired immunodeficiency syndrome. Regardless of the causative species, most cases occur in adult cats with unrestricted outdoor access, although MAC infections have been occasionally reported in exclusively indoor cats. Rapidly Growing Mycobacteria Etiology and Epidemiology The RGM are environmental saprophytes widely distributed as free-living organisms in both terrestrial and aquatic biomes. The RGM are so named as they are able to grow on synthetic culture media within 7 days at 75–113° F (24–45° C). RGM have low inherent pathogenicity and generally tend to cause opportunistic infections in cats, mostly through breaches in the integument, for example, via cat- scratch wounds. They have a low tendency to cause systemic disease unless the host is immunocompromised, although occasionally inhalation of organisms may lead to pneumonia in apparently immunocompetent individuals. The disease manifests in cats primarily as ventral abdominal panniculitis and tends to be caused by the M. smegmatis, M. margaritense, M. fortuitum, and M. chelonae-abscessus groups. VetBooks.ir Mycobacterial Diseases 253 Cases are reported from the Americas (Brazil, southeastern and southwestern United States, Canada), Oceania (Australia and New Zealand), and Europe (Finland, the Netherlands, Germany, and the United Kingdom). The incidence of particular causative organisms varies between geographical regions. M. smegmatis and M. margaritense, followed by M. fortuitum groups, cause most infections in cats in eastern Australia, whereas, in the southwestern United States, M. fortuitum group followed by M. chelonae infections appear to be more common. Cats with a prominent ventral abdominal fat pad appear to have a predisposition toward RGM infection. This is likely due to the preference of the organisms for tissues rich in lipid, which may provide triglycerides for growth and perhaps protection from the host immune response. In cats that do not have a significant amount of subcutaneous fat, the ability to establish experimental infections appears to be limited [3]. Clinical Features Typically, lesions caused by RGM are located in the inguinal region or, less commonly, axillae, flanks, or dorsum. Initially, the infection appears as a circumscribed plaque or nodule of the skin and subcutis. Subsequently, the affected cat develops alopecic areas of thin epidermis which overlies and is adherent to diseased subcutaneous tissue; this results in a characteristic “pepper pot” appearance (Fig. 1). The characteristic focal purple depressions in the skin break down to become fistulae exuding a watery discharge that may become purulent with secondary infection. The lesions may eventually involve the entire ventral abdomen, flanks, perineum, and occasionally the limbs. Internal organs or lymph node involvement is not likely; however, the abdominal wall is rarely involved. Most cats do not have signs of systemic illness unless the skin lesions become secondarily infected with Staphylococcus and Streptococcus spp., in which case the patient may display lethargy, pyrexia, anorexia, weight loss, and reluctance to move. Diagnosis Fine needle aspiration and cytology may establish the presence of pyogranulomatous inflammation, and subcutaneous exudate may be obtained with this technique to allow the culture of the organism, thus establishing the diagnosis. RGM are not typically visible on either Romanowsky-stained cytological samples or hematoxylin and eosin-stained histopathology sections of biopsy tissue. Instead, they are visualized using acid-fast stains, such as Ziehl-Neelsen (ZN) or Fite’s. RGM may be few in number and difficult to visualize in acid-fast stained cytological material, and the diagnosis is not excluded if organisms are not visualized. The organisms may be lost during processing of cytologic and histopathologic VetBooks.ir 254 C. O’Brien Fig. 1 The typical appearance of dermatitis/ panniculitis caused by a rapidly growing mycobacterial species, Mycobacterium smegmatis. (Courtesy of Nicola Colombo) samples as they tend to exist extracellularly in fat vacuoles in tissues. Occasionally, positive results on mycobacterial culture or molecular methods such as polymerase chain reaction (PCR) may be obtained on samples that are “acid-fast bacilli (AFB)negative” on cyto- or histopathological evaluation. Punch biopsies of the skin are usually inadequate for obtaining representative tissue samples, and a deep subcutaneous tissue biopsy from the margin of the lesion is preferred. The histopathologic characteristics of RGM dermatitis/panniculitis include an ulcerated or acanthotic dermis overlying multifocal to diffuse pyogranulomatous inflammation, which tends to extend well into the subcutis. In the pyogranulomas, a rim of neutrophils often surrounds a clear, inner zone of degenerate adipocytes, which may contain scant AFB with an outer collection of epithelioid macrophages (Fig. 2). A mixed inflammatory response, predominantly comprising neutrophils and macrophages, but also containing lymphocytes and plasma cells, is found between each pyogranuloma. AFB may also occasionally be visualized within macrophages but can be very hard to find within tissue sections. When attempting to culture mycobacteria from panniculitis lesions, material swabbed directly from cutaneous draining sinus tracts usually contains high numbers of contaminating skin bacteria, which outcompete the RGM on culture media. Mycobacterial Diseases b VetBooks.ir a 255 Fig. 2 (a) Histopathological aspect of rapidly growing mycobacterial infection: pyogranulomatous inflammation with a rim of neutrophils surrounding a clear, inner zone of degenerate adipocytes, which contain acid fast bacteria (H&E 400×); (b) Ziehl-Neelsen stain of the same sample: rod shaped bacteria are stained in red and can be easily recognised (400×). (Courtesy of Dr. Chiara Noli) Fine-needle samples obtained through intact skin decontaminated with 70% ethanol or surgically collected subcutaneous tissue biopsies are therefore preferred. Uncontaminated samples of RGM grow readily on routine media such as blood [4] and MacConkey agar (without crystal violet), so there is usually no need for the clinician to request “mycobacterial media” culture for these organisms specifically. Treatment and Prognosis Depending on the causative species and the extent of disease when first diagnosed, these infections can be challenging to treat. They often have a high rate of recurrence, frequently require protracted courses of therapy, and may have a substantial incidence of inherent and/or acquired drug resistance. Susceptibility data is especially useful for organisms that may have inherently variable drug susceptibility, such as M. fortuitum, or for recurrent or chronically persistent RGM infections, especially where the cat has undergone prior antibiotic treatment which may have induced acquired drug resistance. Ideally, treatment should begin with one or two oral antimicrobials (doxycycline, a fluoroquinolone, and/or clarithromycin). These are usually chosen empirically until results of culture and susceptibilities are known. In Australia, doxycycline and/or a fluoroquinolone – preferably pradofloxacin – are best, whereas, in the United States, clarithromycin is the drug of choice initially. M. smegmatis group tends to be inherently resistant to clarithromycin, and some isolates may be resistant to the enrofloxacin or ciprofloxacin, although this does not rule out susceptibility to pradofloxacin [5]. Members of the M. fortuitum group are typically susceptible to fluoroquinolones, however, demonstrate variable expression of the erythromycin-inducible methylase (erm) gene which confers macrolide resistance [6]. Approximately 50% of M. fortuitum isolates are susceptible to doxycycline [7]. M. chelonae-abscessus group isolates tend to be resistant to all drugs available for oral dosing apart from clarithromycin and VetBooks.ir 256 C. O’Brien linezolid. Where indicated by drug susceptibility data, refractory cases may be treated with clofazimine, amikacin, cefoxitin, or linezolid. It is recommended to commence treatment at standard dose rates increased slowly to the high end of the dose range, unless adverse effects are observed. Treatment duration is variable, but it is recommended to continue therapy for 1–2 months past resolution of all clinical signs. Some animals with recalcitrant lesions benefit from en bloc resection of isolated areas of infection, often necessitating reconstructive surgery [8] or vacuum-assisted wound closure [9, 10]. Public Health Risks Zoonotic transmission of RGM organisms from infected animals to humans is very unlikely. There is one report of M. fortuitum infection in an otherwise healthy middle-aged woman, after a cat bite to the forearm [11]. Slowly Growing Mycobacteria The SGM taxon includes a large number of opportunistic environmental species: the obligate pathogens, M. leprae and M. lepromatosis, and the members of the M. tuberculosis complex. There are also a number of fastidious species included – traditionally classified as the causative species of “feline leprosy” – that are incapable of growing in axenic culture; thus, their epidemiological niche is unclear. Tuberculous Mycobacteria Cats are naturally resistant to M. tuberculosis, but occasional infections likely transmitted directly from humans are reported [12]. Disease in cats is most commonly caused by M. bovis and M. microti [13]. M. bovis has worldwide endemicity. However, much of Continental Europe, parts of the Caribbean, and Australia are free of the disease due to widespread surveillance, slaughter of test-positive cattle, the pasteurization of milk, and the absence of a wildlife host. M. microti is endemic to Europe and the United Kingdom (UK). Its main reservoir appears to be voles, shrews, wood mice, and other small rodents [14]. The exact route of transmission of these MTB species to cats is unclear. Numerous potential rodent prey species collected from areas of southwest England were found to be infected with M. bovis [15]. Suspected nosocomial contamination of surgical wounds has been reported [16]. MAC and Other Slowly Growing Saprophytes Disease in cats is caused by several saprophytic slowly growing mycobacterial species, mostly members of the MAC, which are found worldwide in water sources and soil. Certain slowly growing species are more common in some environmental VetBooks.ir Mycobacterial Diseases 257 niches or particular geographical areas, for example, M. malmoense or biofilms with M. intracellulare in the UK and Sweden. Some have highly restricted, focal areas of endemicity, for example, M. ulcerans infection. As with MTB complex, the clinical picture is determined by the route of infection. Cats likely acquire skin lesions via transcutaneous inoculation of contaminated environmental material. Most cats with slow-growing mycobacterial infections have unrestricted outdoor access, and almost all of these cases had no overt predisposing conditions. Fastidious Mycobacteria “Feline leprosy” has been diagnosed in New Zealand, Australia, western Canada, the UK, southwestern United States, continental Europe, New Caledonia, the Greek islands, and Japan. Historically, New Zealand and Australia have reported the highest number of cases worldwide. Genetic studies have identified the involvement of several “non-culturable” species of mycobacteria: M. lepraemurium, Candidatus “M. tarwinense,‘ [17, 18] Candidatus “M. lepraefelis,‘ [19] and M. visibilis, although the latter has not been reported for many years [20]. M. lepraemurium tends to cause disease in young male cats, whereas Candidatus “M. tarwinense” and Candidatus “M. lepraefelis” are more likely to cause disease in middle-aged to older cats. There is no gender preponderance for Candidatus “M. tarwinense” infection, whereas Candidatus “M. lepraefelis” is slightly more likely to cause disease in males. Clinical Features The majority of cats with SGM infection have solitary or multiple nodular skin lesions and/or local lymphadenopathy, especially of the head, neck, and/or limbs (Fig. 3). Ulceration of cutaneous lesions and the skin overlying affected lymph nodes may be Fig. 3 Large, ulcerated nodules on the lateral thigh of a young male cat with Mycobacterium lepraemurium infection. Despite the widespread nature of the cutaneous lesions, this cat was cured with multidrug therapy including rifampicin and clofazimine. (Courtesy of Dr. Mei Sae Zhong) VetBooks.ir 258 C. O’Brien observed, and infection may occasionally involve contiguous muscle and bone, which is more often the case with MTB complex species than other causative agents. In some cases, the dermal lesions may be widespread, involving many cutaneous sites. Host factors (age, concurrent illness, immunological status), the causal species, or the route and size of the inoculum may influence the nature of the disease. If systemic disease is detected, the most common causative agents are either the MTB complex mycobacteria (especially in the UK and New Zealand) or members of the MAC. Rarely, systemic infections by other mycobacterial species, including other slowly growing saprophytes and Candidatus “M. lepraefelis,” have been documented. Diagnosis Differential diagnoses of nodular skin and subcutaneous lesions include Nocardia and Rhodococcus spp. (which may also be acid-fast), fungi, or algal infections and primary or metastatic neoplasia. There are no pathognomonic clinical features that differentiate mycobacterial infections from other etiologies, and collection of representative tissue samples for cytology or histopathology and microbiology is necessary for the diagnosis. It is vital in areas endemic for the MTB complex that the diagnosis is not based simply on cytologic or histopathologic findings. An attempt to identify the causative agent should be made in every case, ideally via a mycobacterium reference laboratory or equivalent, especially where mandatory reporting of such cases may result in compulsory euthanasia. The diagnosis of cutaneous infections caused by SGM is often relatively simple, provided there is a high index of suspicion. Personal protective equipment should be worn during any procedure which involves handling of discharging or ulcerated lesions and/or surgical or necropsy tissues, when members of the MTB complex are a possible cause of disease. Ideally, at the time of biopsy sampling for histopathology, a piece of fresh tissue wrapped in sterile saline-moistened gauze swabs placed in a sterile container should be collected, if microbiological processing is needed. The pathology laboratory should ideally be notified before submission, as SGM culture and identification requires specialized expertise. Romanowsky-stained cytological samples of cutaneous nodules will demonstrate granulomatous to pyogranulomatous inflammation, and mycobacteria are recognized by their characteristic “negatively staining” appearance (Fig. 4), usually located within macrophages. As with the RGM, SGM are not typically visible on Romanowsky-stained cytological or hematoxylin and eosin-stained histopathology sections, except M. visibile and Candidatus “M. lepraefelis.” Instead, Ziehl-Neelsen (ZN) staining (Fig. 5) or similar (e.g. Fite’s) is required. Depending on mycobacterial species and host immune response, bacterial numbers may be variable. MTB complex organisms produce characteristic solitary to coalescing granulomas (“tubercules”). Granulation tissue surrounds a layer of mixed inflammatory cells, consisting of macrophages, neutrophils, lymphocytes, and plasma cells. The VetBooks.ir Mycobacterial Diseases 259 Fig. 4 Numerous macrophages with cytoplasm filled with many achromatic rod-shaped areas (Diff Quick, 1000×). (Courtesy of Dr. Francesco Albanese) Fig. 5 Many brightly red and rod-shaped Mycobacteria are well recognizable with Ziehl-Neelsen staining (1000×). (Courtesy of Dr. Francesco Albanese) center of the granuloma contains epithelioid macrophages and some neutrophils, with variable but usually low numbers of AFB, with or without necrotic tissue. Cutaneous MAC infections cause pyogranulomatous or granulomatous inflammation with a variable fibroblastic response. The fibroblastic reaction may, on occasion, be so pronounced as to make it difficult to differentiate the disease from an inflamed fibrosarcoma (so-called “mycobacterial pseudotumor”) [21]. AFB found both within macrophages and spindle cells identify the underlying etiology in these cases (Fig. 6). In the absence of a prominent fibroblastic response, lesions may resemble lepromatous leprosy. The pathological picture of feline leprosy is subdivided into multi-bacillary (lepromatous) and pauci-bacillary (tuberculoid) forms [22]. “Multi-bacillary” leprosy is thought to correspond with a weak cell-mediated immune (CMI) response. Typically, many foamy or multinucleate macrophages, containing huge numbers of mycobacteria, are observed. There is no necrosis, and lesions contain virtually no lymphocytes and plasma cells. “Pauci-bacillary” leprosy, in which moderate to few VetBooks.ir 260 C. O’Brien Fig. 6 Histopathological appearance of MTB complex infection: granulomas consisting of macrophages, neutrophils, lymphocytes and plasma cells. The center of the granuloma contains epithelioid macrophage (H&E 400×) (Courtesy of Dr. Chiara Noli) observable AFB are found within pyogranulomatous inflammation dominated by epithelioid histiocytes, is thought to occur with a more effective CMI response. Moderate numbers of lymphocytes and plasma cells are also observed, with multifocal to coalescing necrosis. Involvement of peripheral nerves, a feature of human leprosy, is not seen in cats. Except where samples have become contaminated with environmental mycobacteria, molecular methods, such as PCR and sequencing, can provide a highly accurate diagnosis on fresh or frozen tissue, formalin-fixed paraffin-embedded tissue sections, and Romanowsky-stained cytology slides [23]. It should be remembered that for samples in which no AFB are visualized microscopically, mycobacterial infections cannot be excluded with a negative PCR result. A feline IFN-γ ELISPOT test is currently commercially available [24]. This test utilizes both bovine tuberculin and ESTAT6/CFP10 for the identification of cats infected with either M. bovis or M. microti and is able to differentiate the two mycobacteria. It is reported as having a sensitivity of 90% for detecting feline M. bovis infections, 83.3% sensitivity for detecting feline M. microti infections, and 100% specificity for both. Serum antibody tests (multi-antigen print immune-assay (MAPIA), TB STAT- PAK, and Rapid DPP VetTB) have been evaluated in cats with TB [25]. Overall sensitivity was 90% for detection of M. bovis infection and greater than 40% for M. microti, with a specificity of 100%. It is important to remember that these tests do not explicitly differentiate active from latent infection or prior exposure. Culture of organisms from clinical samples obtained from cats with appropriate signs and diagnostic findings remains the gold standard for the diagnosis of active TB. Treatment Controlled studies of feline mycobacteriosis treatment are lacking, and the existing literature consists of a few retrospective observational case series and case reports. Mycobacterial Diseases 261 VetBooks.ir Table 1 Drugs typically chosen to treat feline mycobacterial infections Drug Clofazimine Dose 25 mg/cat PO q 24 h or 50 mg/ cat q 48 h Clarithromycin 62.5 mg/cat PO q 12 h 5–15 mg/kg PO q 24 h 10 mg/kg PO q 24 h Azithromycin Rifampicin Doxycycline Enrofloxacin Marbofloxacin Orbifloxacin Pradofloxacin Moxifloxacin 5–10 mg/kg PO q 12 h 5 mg/kg PO q 24 h 2 mg/kg PO q 24 h 7.5 mg/kg PO q 24 h 7.5 mg/kg PO q 24 h 10 mg/kg PO q 24 h Side effects/comments Skin and body fluid discoloration (pink-brown), photosensitization, pitting corneal lesions, nausea, vomiting, and abdominal pain Possible hepatotoxicity Monitor serum hepatic enzymesa Cutaneous erythema and edema, hepatotoxicity, diarrhea, and/or vomiting, neutropenia, thrombocytopenia Vomiting, diarrhea, abdominal pain, hepatotoxicity Hepatotoxicity and/or inappetence, cutaneous erythema/ pruritus, anaphylaxis Monitor serum hepatic enzymesa Hydrochloride or hyclate formulations may cause esophageal irritation and possibly stricture Enrofloxacin may cause retinal toxicity in cats; marbofloxacin or orbifloxacin are preferred if available Most M. avium complex organisms are resistant to second-generation fluoroquinolones Give without food unless gastrointestinal side effects occur Vomiting and anorexia; dose can be divided 12 hourly and/or administered with food Alanine transferase and alkaline phosphatase a There have been occasional reports of spontaneous resolution of M. lepraemurium infection; [26, 27] however, the vast majority of SGM infections require treatment to achieve a cure. Table 1 lists the drugs and doses typically chosen to treat feline mycobacteriosis. The initiation of empirical treatment is required in almost all cases of SGM infection, as identification of the causative mycobacterium may take weeks to months (or may not be available at all). The choice of initial treatment will depend on [1] the suspected etiological agent, [2] owner factors such as finances and ability/ willingness to medicate the cat orally for an extended period, and [3] the presence of comorbidities that may restrict the use of certain drugs, for example, hepatic disease when using rifampicin. Therapy should include at least rifampicin, clarithromycin (or azithromycin), and/or pradofloxacin (or moxifloxacin). In areas where infection with the fastidious organisms is common the inclusion of clofazimine, if available, would also be a reasonable choice. Ethambutol and isoniazid have been used to treat feline TB, although toxicity tends to limit their use. They tend only to be prescribed if there is drug resistance to the more commonly utilized agents. If the infection is restricted to a localized cutaneous site, surgical excision may be a beneficial adjunct to antibiotic therapy. Medical treatment can be subsequently modified depending on identification of the mycobacterial species involved, response to treatment, and/or, if available, the VetBooks.ir 262 C. O’Brien results of drug susceptibility testing. Therapy should extend for at least 2 months post-surgical resection or beyond resolution of clinical signs. Unless diagnosed with MTB complex infection, quarantine of the cat is not necessary. Some of the drugs, especially clofazimine, induce photosensitivity; it is recommended that owners keep the cat indoors in the summer months. Prognosis Localized cutaneous infection caused by all slowly growing species has a good prognosis if treated promptly with a combination of appropriate antibiotics, and if possible surgical resection. If cutaneous disease progresses to systemic infection, the prognosis becomes significantly worse. Treatment is potentially expensive and time-consuming. Cats can be notoriously tricky to medicate, and the provision of multidrug therapy for many months may also affect the outcome. Public Health Risks The only SGM that appears to carry a definite risk of cat-to-human transfer is M. bovis, although this risk seems to be low. A report from the UK details the infection in four people (two clinically and two sub-clinically affected) associated with an infected pet cat [28]. A laboratory worker seroconverted after exposure to research cats that were infected after accidentally being fed infected meat [29]. At this time, instances of cat-to-human transmission of M. microti infection have not been reported. There is one report of a person contracting M. marinum secondary to a cat scratch [30]. However, this likely represented mechanical inoculation, rather than true zoonotic transfer. Likewise, there appears to be almost no risk of humans acquiring infections from any of the fastidious organisms from cats; however, as the ecology and transmission of these mycobacterial species are not understood, it is difficult to determine their potential for zoonotic transfer completely. The Advisory Board on Cat Diseases (based in Europe) recommends that all people in contact with an infected cat should be made aware of the potential but low risk of zoonotic transfer of feline mycobacteriosis [31]. As a minimal precaution, the use of gloves is recommended when treating these animals. This is especially important for anyone in contact with the cat who is immunocompromised. Veterinary staff should utilize personal protective equipment when handling cats with cutaneous lesions, collecting biopsies, or performing necropsy studies. References 1. Gupta RS, Lo B, Son J. Phylogenomics and comparative genomic studies robustly support division of the genus Mycobacterium into an emended genus Mycobacterium and four novel genera. Front Microbiol. 2018;9:67. VetBooks.ir Mycobacterial Diseases 263 2. Fedrizzi T, Meehan CJ, Grottola A, Giacobazzi E, Serpini GF, Tagliazucchi S, et al. Genomic characterization of nontuberculous mycobacteria. Sci Rep. 2017;7:45258. 3. Lewis DT, Hodgin EC, Foil S, Cox HU, Roy AF, Lewis DD. Experimental reproduction of feline Mycobacterium fortuitum panniculitis. Vet Dermatol. 1994;5(4):189–95. 4. Drancourt M, Raoult D. Cost-effectiveness of blood agar for isolation of mycobacteria. PLoS Negl Trop Dis. 2007;1(2):e83. 5. Govendir M, Hansen T, Kimble B, Norris JM, Baral RM, Wigney DI, et al. Susceptibility of rapidly growing mycobacteria isolated from cats and dogs, to ciprofloxacin, enrofloxacin and moxifloxacin. Vet Microbiol. 2011;147(1–2):113–8. 6. Nash KA, Andini N, Zhang Y, Brown-Elliott BA, Wallace RJ. Intrinsic macrolide resistance in rapidly growing mycobacteria. Antimicrob Agents Chemother. 2006;50(10):3476–8. 7. Brown-Elliott B, Philley J. Rapidly growing mycobacteria. Microbiol Spectr. 2017;5:TNMI7-0027-2016. 8. Malik R, Wigney DI, Dawson D, Martin P, Hunt GB, Love DN. Infection of the subcutis and skin of cats with rapidly growing mycobacteria: a review of microbiological and clinical findings. J Feline Med Surg. 2000;2(1):35–48. 9. Guille AE, Tseng LW, Orsher RJ. Use of vacuum-assisted closure for management of a large skin wound in a cat. J Am Vet Med Assoc. 2007;230(11):1669–73. 10. Vishkautsan P, Reagan KL, Keel MK, Sykes JE. Mycobacterial panniculitis caused by Mycobacterium thermoresistibile in a cat. JFMS Open Rep. 2016;2(2):2055116916672786. 11. Ngan N, Morris A, de Chalain T. Mycobacterium fortuitum infection caused by a cat bite. N Z Med J. 2005;118(1211):U1354. 12. Alves DM, da Motta SP, Zamboni R, Marcolongo-Pereira C, Bonel J, Raffi MB, et al. Tuberculosis in domestic cats (Felis catus) in southern Rio Grande do Sul. Pesquisa Veterinária Brasileira. 2017;37(7):725–8. 13. Gunn-Moore DA, McFarland SE, Brewer JI, Crawshaw TR, Clifton-Hadley RS, Kovalik M, et al. Mycobacterial disease in cats in Great Britain: I. Culture results, geographical distribution and clinical presentation of 339 cases. J Feline Med Surg. 2011;13(12):934–44. 14. Cavanagh R, Begon M, Bennett M, Ergon T, Graham IM, De Haas PE, et al. Mycobacterium microti infection (vole tuberculosis) in wild rodent populations. J Clin Microbiol. 2002;40(9):3281–5. 15. Delahay RJ, Smith GC, Barlow AM, Walker N, Harris A, Clifton-Hadley RS, et al. Bovine tuberculosis infection in wild mammals in the south-west region of England: a survey of prevalence and a semi-quantitative assessment of the relative risks to cattle. Vet J. 2007;173(2):287–301. 16. Murray A, Dineen A, Kelly P, McGoey K, Madigan G, NiGhallchoir E, et al. Nosocomial spread of mycobacterium bovis in domestic cats. J Feline Med Surg. 2015;17(2):173–80. 17. Fyfe JA, McCowan C, O'Brien CR, Globan M, Birch C, Revill P, et al. Molecular characterization of a novel fastidious mycobacterium causing lepromatous lesions of the skin, subcutis, cornea, and conjunctiva of cats living in Victoria, Australia. J Clin Microbiol. 2008;46(2): 618–26. 18. O’Brien CR, Malik R, Globan M, Reppas G, McCowan C, Fyfe JA. Feline leprosy due to Candidatus ‘Mycobacterium tarwinense’ further clinical and molecular characterisation of 15 previously reported cases and an additional 27 cases. J Feline Med Surg. 2017;19(5): 498–512. 19. O'Brien CR, Malik R, Globan M, Reppas G, McCowan C, Fyfe JA. Feline leprosy due to Candidatus ‘Mycobacterium lepraefelis’: further clinical and molecular characterisation of eight previously reported cases and an additional 30 cases. J Feline Med Surg. 2017;19(9):919–32. 20. Appleyard GD, Clark EG. Histologic and genotypic characterization of a novel Mycobacterium species found in three cats. J Clin Microbiol. 2002;40(7):2425–30. 21. Miller MA, Fales WH, McCracken WS, O'Bryan MA, Jarnagin JJ, Payeur JB. Inflammatory pseudotumor in a cat with cutaneous mycobacteriosis. Vet Pathol. 1999;36(2):161–3. 22. Malik R, Hughes MS, James G, Martin P, Wigney DI, Canfield PJ, et al. Feline leprosy: two different clinical syndromes. J Feline Med Surg. 2002;4(1):43–59. VetBooks.ir 264 C. O’Brien 23. Reppas G, Fyfe J, Foster S, Smits B, Martin P, Jardine J, et al. Detection and identification of mycobacteria in fixed stained smears and formalin-fixed paraffin-embedded tissues using PCR. J Small Anim Pract. 2013;54(12):638–46. 24. Rhodes SG, Gruffydd-Jones T, Gunn-Moore D, Jahans K. Adaptation of IFN-gamma ELISA and ELISPOT tests for feline tuberculosis. Vet Immunol Immunopathol. 2008;124(3–4):379–84. 25. Rhodes SG, Gunn-Mooore D, Boschiroli ML, Schiller I, Esfandiari J, Greenwald R, et al. Comparative study of IFNgamma and antibody tests for feline tuberculosis. Vet Immunol Immunopathol. 2011;144(1–2):129–34. 26. O'Brien CR, Malik R, Globan M, Reppas G, Fyfe JA. Feline leprosy due to Mycobacterium lepraemurium: further clinical and molecular characterization of 23 previously reported cases and an additional 42 cases. J Feline Med Surg. 2017;19(7):737–46. 27. Roccabianca P, Caniatti M, Scanziani E, Penati V. Feline leprosy: spontaneous remission in a cat. J Am Anim Hosp Assoc. 1996;32(3):189–93. 28. England PH. Cases of TB in domestic cats and cat-to-human transmission: risk to public very low. 2014. Available from: https://www.gov.uk/government/news/ cases-of-tb-in-domestic-cats-and-cat-to-human-transmission-risk-to-public-very-low. 29. Isaac J, Whitehead J, Adams JW, Barton MD, Coloe P. An outbreak of Mycobacterium bovis infection in cats in an animal house. Aust Vet J. 1983;60(8):243–5. 30. Phan TA, Relic J. Sporotrichoid Mycobacterium marinum infection of the face following a cat scratch. Australas J Dermatol. 2010;51(1):45–8. 31. Lloret A, Hartmann K, Pennisi MG, Gruffydd-Jones T, Addie D, Belak S, et al. Mycobacterioses in cats: ABCD guidelines on prevention and management. J Feline Med Surg. 2013;15(7):591–7. VetBooks.ir Dermatophytosis Karen A. Moriello Abstract Feline dermatophytosis is a superficial fungal skin disease of cats. The primary mode of transmission is via direct contact or traumatic fomite inoculation. Microsporum canis is the primary pathogen of cats although outdoor cats may contract Trichophyton spp. infections. Diagnosis is based upon use of complementary diagnostic tests. Evidence-based studies have concluded there is no one “gold standard diagnostic test.” Contrary to popular belief, evidence-based studies found that Wood’s lamp examinations are positive in >91% of untreated cats, making it a highly useful point-of-care diagnostic test when combined with direct examination of hair and scales. PCR analysis of infective material is also diagnostic. Fungal culture is needed for species identification. Topical antifungal therapy is necessary to disinfect hairs, minimize disease transmission, and prevent environmental contamination. Systemic antifungal therapy eradicates the disease within the hair follicle. Evidence-based studies have shown that environmental disinfection is easily done via continued removal of cat hair and debris. Spores do not multiply in the environment or invade homes; spores are easily removed from soft and hard surfaces via washing with a detergent. Over-the-counter home disinfectants (i.e., bathroom cleaners) labelled as efficacious against Trichophyton spp. are recommended over household bleach which can be a human and animal health hazard. This is a low-level zoonotic skin disease that may cause superficial skin lesions that are treatable and curable in people. K. A. Moriello (*) School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA e-mail: Karen.moriello@wisc.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_13 265 266 K. A. Moriello VetBooks.ir Introduction Dermatophytosis is a contagious, superficial fungal skin disease of skin, hair, scales, and claws. It is non-life threatening, treatable, and curable and is a low-level zoonotic disease, i.e., it does not cause death and is easily treated. The disease will resolve without treatment in otherwise healthy animals. Treatment is recommended to shorten the course of the infection and limit the risk of transmission to other susceptible hosts. The two major goals of this chapter are to (1) summarize key aspects of this disease from recent evidence-based studies and (2) provide evidence to counter many “Internet” myths surrounding this disease that result in poor treatment, unwarranted client worries, and, in worst-case scenarios, euthanasia of cats and kittens. Pathogens of Importance and New Classifications Dermatophytes are aerobic fungi that invade and infect keratinized skin, hair, scales, and nails. These organisms are classified by host preference: anthropophilic (humans), zoophilic (animals), and geophilic (soil). Dermatophytes are also classified by different names depending upon whether or not they are in an asexual state (anamorph) or a sexual state (teleomorph) [1, 2]. For example, Microsporum canis is an anamorphic species that belongs to the teleomorphic Arthroderma otae complex (M. canis, M. ferrugineum, M audouinii) [3]. The naming of anamorphs is based upon fungal culture macro- and micro-characteristics. Recently molecular testing has found many species to be one and the same. In 2011, the Amsterdam Declaration on Fungal Nomenclature (One Fungus = One Name) was adopted, and reclassification is currently underway [4]. Trichophyton and Microsporum are being reclassified into the genus Arthroderma. Clinicians need to be aware of this, as clinical manuscripts are increasingly using new nomenclature. This chapter will use the traditional names. The most important pathogen of cats is Microsporum canis. Less commonly cats can be infected by Trichophyton spp. and M. gypseum. It has been well established that dermatophytes are not part of the normal fungal flora of cats by both traditional and molecular tests [5–7]. Prevalence True disease prevalence is unknown as this is not a reportable disease. A recent review of 73 papers from 29 countries revealed prevalence data was highly biased depending upon the source of the cats, whether studies were prospective or retrospective, whether data was collected and interpreted before or after the recognition of fomite carriage, and other inclusion criteria [2]. The most helpful data on prevalence is from studies where true disease was confirmed. These studies consistently found an overall low prevalence (<3%) in clinical VetBooks.ir Dermatophytosis 267 practice and shelters (Box 1). In one study from the United States (n = 1407 cats), the overall prevalence of confirmed disease was 2.4% [8], while in a Canadian study (n = 111 cats), it was 3.6% [9]. In a study from the United Kingdom (n = 154 cats), it was 1.3% [10]. More interestingly, in another study from the United Kingdom, the medical records of 142, 576 cats found that it was not even listed as a common skin disease, even though 10.4% of cats were presented for skin disease [11]. In a study looking at the chronic pruritic cats (n = 502), only 2.1% of cats were diagnosed with the disease [12]. Finally, in a retrospective study of cats admitted to an open admission animal shelter (n = 5644), disease prevalence was 1.6% over a consecutive 24-month period of time [13]. Box 1: Key Points on Disease Prevalence • Dermatophytosis is an uncommon cause of skin lesions in cats (<3%). • It is untrue that “it is ringworm until proven otherwise!” • It is a common skin disease in kittens. Risk Factors Risk factors for dermatophytosis include warm, humid environments, young age, and group housing (e.g., animal shelters or catteries) [14–21]. Anecdotal reports of “old age” or “older cats” with underlying age-related diseases being predisposed to dermatophytosis were not supported by evidence [2]. Seropositive FeLV or FIV cats have not been shown to be at increased risk of infection [22]. The development of dermatophytosis in cats receiving immunosuppressive treatment for pemphigus foliaceus was not reported in two large studies [23, 24]. Given the widespread use of feline cyclosporine, there is only one cat reported to have developed disease while receiving this drug [25]. With respect to breed predispositions, Persian cats are often listed as being “predisposed”; however, this breed is over-represented in prevalence and treatment studies. Subcutaneous dermatophyte infections, although rare, are almost exclusively reported in long haired breeds. ey Aspects of the Pathogenesis, Transmission, and Immune K Response to Infection Pathogenesis of Infection The infective form of dermatophytes is an arthrospore which is formed by fragmentation of fungal hyphae into smaller infective units. There are three stages of a dermatophyte infection [2]. First, arthroconidia adhere to corneocytes which can occur within 2–6 hours of exposure [26–28]. Second, fungi start to germinate with germ VetBooks.ir 268 K. A. Moriello tubes emerging from the arthroconidia followed by penetration of the stratum corneum. Finally, there is invasion of keratinized structures; dermatophyte hyphae invade and grow in multiple directions including the hair follicle unit. Hyphae can start to form arthroconidia within 7 days. Obvious clinical lesions are usually seen within seven to 21 days. Transmission Development of M. canis lesions has been studied in direct application models of infection and in co-habitant natural exposure experiments and offers practical insights on disease transmission [29–35]. In direct application models, it was extremely difficult to establish infections unless there was a critical mass of infective spores (>104 spores per site). Successful infection required micro-trauma and occlusion of the site. It was not possible to infect cats/kittens that were allowed to remove the infective inoculum via grooming. Positive Wood’s lamp fluorescence was present in 100% of experimentally infected cats and was noted as early as 5 to 7 days post infection. In co-habitant models, a highly social infected cat was added to a group of healthy cats, and lesion development followed a clear pattern. Lesions developed over time in all cats, starting with the most social cats. All lesions began on the face and ears and then progressed. In studies where healthy cats were housed in contaminated environments but did not experience any skin micro-trauma, cats became culture positive but did not develop lesions. Cats became culture negative after washing or simply being moved to a clean room and allowed to groom. It is now well established that the primary mode of disease transmission is via direct contact with another infected animal. Grooming is an important innate protective mechanism against disease transmission. Micro-trauma is an important prerequisite for establishment of a successful infection. Increased micro-trauma to the skin from pruritus or self-trauma, humidity, and ectoparasites all contribute to conditions optimal for disease development. Transmission from contaminated fomites is a risk factor if it induces micro-trauma (e.g., grooming tools) or if the cat is in a contaminated environment and self-traumatizes itself (e.g., is pruritic from ectoparasites). Transmission from contaminated environments is not an efficient mode of transmission in the absence of micro-trauma and moisture. Immunity and Recovery from Infection Cats develop both a cell-mediated and humoral immune response to dermatophyte infections [35–37]. Intradermal and in vitro studies show that recovery from infection depends upon the development of a strong cell-mediated immune response. Cell-mediated immunity is important for protection against reinfection. Studies have shown that reinfection of infected but cured cats was possible, but required a greater number of spores, more occlusion, or both. The subsequent infections were milder and resolved much sooner. Dermatophytosis 269 VetBooks.ir Clinical Findings There are no “pathognomonic” clinical signs of feline dermatophytosis. The clinical signs of dermatophytosis reflect the pathogenesis of the disease: invasion of keratinized structures of the skin. Clinical signs are also impacted by the age and overall physiological health. For example, kittens with limited infections are at risk for developing more widespread lesions if they contract upper respiratory infections or gastrointestinal disease. Practical Approach to “Clinical Signs” Dermatophytosis severity reflects the overall global health of a cat. From that perspective, there are different clinical presentations of dermatophytosis: simple infections, complicated infections, and culture-positive lesion-free cats. Simple infections are any disease that occurs in an otherwise healthy cat. Lesion severity tends to be limited, and these cats respond well to treatment. It is likely that many kittens develop limited lesions of dermatophytosis that self-resolve and never get diagnosed. Complicated infections are more difficult to treat because lesions tend to be more severe and the cat/kitten has a concurrent medical disease, develops a concurrent disease shortly after diagnosis that explains the severity of the skin disease, and/or has some other complicating factor making treatment challenging (e.g., bandage requirements that make topical therapy options limited.) A “complicated infection” is any case where treatment is not straightforward. Culture-positive lesion-free cats are either cats that are fomite carriers or cats that have subtle lesions that were missed at the time of initial examination. When lesion-free, culture-positive cats are identified, re-examine the cat with a Wood’s lamp and look for lesions. Fomite carriage is easily identified by simply washing the cat, moving it to a clean environment, and repeating a culture. True fomite carriage cats will be culture negative; a single bath will not remove infective spores from the hair coat with true infection. Common Findings Lesions tend to be asymmetrical. As mentioned above, observational studies on cohabitant infection models documented that lesions tend to start on the face, ears, and muzzle and then progress to the paws and tail (Figs. 1, 2, and 3) [34, 38]. Lesions can be focal or multifocal. Hair loss may be mild, and sometimes, the primary client concern is excessive hair loss. Some cats have a history of vomiting hair balls or constipation. Scaling is common and sometimes can be marked (Figs. 4 and 5). In severe cases, there can be exudative paronychia. The inflammatory reaction can vary from mild to marked, and diffuse erythema may be present. Follicular plugging and hyperpigmentation are somewhat uncommon in cats but most likely to be seen in cats with dermatophytosis. Microsporum canis can cause comedone-like lesions VetBooks.ir 270 K. A. Moriello Fig. 1 Facial lesions on a young cat with dermatophytosis. (Courtesy of Dr. Rebecca Rodgers) Fig. 2 Alopecia and scaling on the pinna of a Persian cat with dermatophytosis. (Courtesy of Dr. Chiara Noli) in young cats. Pruritus is variable and can be intense and may mimic areas of eosinophilic pyotraumatic dermatitis. Uncommon Presentations Uncommon clinical presentations in cats include cases clinically identical to pemphigus foliaceus, including symmetrical crusting over the face and ear and exudative paronychia. Unilateral or bilateral pinnal pruritus is another unique clinical presentation. Infected hairs are on the ear margins or in the “bell” of the ear. Rarely, VetBooks.ir Dermatophytosis Fig. 3 Alopecia on the back and tail in an advanced case of dermatophytosis in a Persian cat. (Courtesy of Dr. Chiara Noli) Fig. 4 Same cat as in Figure 2: patch of alopecia with very mild scaling. (Courtesy of Dr. Chiara Noli) Fig. 5 Shorthaired cat with dermatophytosis showing a focal patch of alopecia and thick scales. (Courtesy of Dr. Chiara Noli) 271 VetBooks.ir 272 K. A. Moriello Fig. 6 Ulcerated nodule due to a dermatophytic mycetoma. (Courtesy of Dr. Andrea Peano) diffuse multifocal areas of waxy hyperpigmentation have been observed. Nodular dermatophytosis has been most commonly reported in Persian cats (Fig. 6). There is usually a history of prior dermatophytosis but not always. These may or may not ulcerate and drain. Diagnosis Dermatophytosis cannot be diagnosed based upon clinical signs. A recent evidencebased review concluded that no one test could be identified as the “gold standard.” Current recommendations are to use multiple complementary diagnostics [2]. Diagnostics for dermatophytosis are divided into two major categories: point-ofcare (POC) and reference laboratory (RL) testing. Complete blood counts, serum chemistry panels, urinalysis, and diagnostic imaging are not helpful for confirming the presence or absence of dermatophytosis. These tests are helpful when evaluating a cat with a complicated infection. Point-of-Care Diagnostics There are three key complementary POC diagnostic tests and tools: dermoscopy, Wood’s lamp examination, and direct examination of hair/scales. Dermoscopy and Wood’s lamp examinations are tools used to find suspect hairs for direct examination. If infection can be confirmed via direct examination of hair shafts and scale, treatment can be initiated at the time of presentation. VetBooks.ir Dermatophytosis 273 Dermoscopy Dermoscopy (Figs. 7 and 8) is a non-invasive POC tool that allows for magnification and illumination of the skin. The primary use of dermoscopy is to find hairs for direct examination. This tool can be used with or without a Wood’s lamp examination. Two studies found that M. canis-infected hairs have a unique appearance [39, 40]. Infected hairs are opaque, slightly curved, or broken with a homogenous thickness (Fig. 9). Hairs are easier to find in light colored cats than in darkly colored cats. The biggest obstacle to the use of this test is patient cooperation. ood’s Lamp Examination W A Wood’s lamp is a POC diagnostic tool whose primary usage is to find hairs for direct examination or to lesion resolution in M. canis infected cats. A Wood’s lamp is a plug-in lamp with an ultraviolet light spectrum of 320–400 nm wavelength [41]. In Fig. 7 Hand-held dermoscope. (Courtesy of Dr. Fabia Scarampella) Fig. 8 Cat being examined with a dermoscope. (Courtesy of Dr. Fabia Scarampella) VetBooks.ir 274 K. A. Moriello Fig. 9 Infected hairs visualized with a dermoscope. (Courtesy of Dr. Fabia Scarampella). Arrows required to indicate infected hairs veterinary dermatology, the only fungal pathogen of importance that fluoresces is M. canis. The characteristic green fluorescence of M. canis-infected hairs is due to a watersoluble pigment located within the cortex or medulla of the hair [42–44]. The fluorescence is the result of a chemical interaction that occurs as a result of the infection and is not associated with spores or infective material. An evidence-based review of literature has found that many commonly held beliefs are incorrect about the usefulness of Wood’s lamp examination, prevalence of positive fluorescence, and overall usefulness as a point-of-care “test”; this is tool and it cannot be emphaized enough. Statements such as “less than 50% of strains fluoresce” are based upon retrospective studies of random source diagnostic specimens [15, 45–47]. When data from 30 experimental infection studies and spontaneous disease studies was examined, results were surprisingly different [2]. There was 100% fluorescence in cats with experimental infections, and in studies involving spontaneous disease in untreated animals, it was >91%. Not unexpectedly, positive fluorescence was less common in cats under treatment. Fluorescing “tips” are a common finding in cats that have been treated and cured. It is simply residual pigment left over from the infection within the hair follicle (Fig. 10). In the author’s experience, the use of a Wood’s lamp is not unlike mastering sample acquisition for skin/ear cytology and using a microscope. See Box 2 for helpful hints on using a Wood’s lamp. It cannot be stressed enough that this is a skill that can be learned. With the “right” Wood’s lamp and practice, this is a helpful tool for finding suspect hairs (Figs. 11a, b). It is immensely helpful in finding lesions that are otherwise missed in room light (Fig. 12). Fluorescing hairs are commonly found in untreated infections; fluorescence may be more difficult to find in treated animals. False-positive and false-negative results are commonly due to inadequate equipment, lack of magnification, patient compliance, poor technique, or lack of 275 VetBooks.ir Dermatophytosis SKIN Fig. 10 Schematic of Wood’s lamp positive hairs (from left to right). Positive fluorescence is found on the hair shafts only. Uninfected hairs show no fluorescence. Early infected hairs show fluorescence in the proximal part of the hair. As the infection progresses, the entire hair shaft will fluoresce. When the infection has been eradicated in the hair follicle, the proximal portion of the hair shaft will no longer fluoresce (see hair with blue outline). This is an indication of a good response to treatment. Cured cats will often have some residual “glowing tips” because the pigment is retained in the medulla or cortex (yellow = uninfected; green = fluorescent, thus infected). Glowing tip hairs may or may not be culture positive a b Fig. 11 Kitten with dermatophytosis: (a) mild lesions evident around the eyes; (b) evident fluorescence on the same sites with Wood light examination. (Courtesy of Dr. Laura Mullen) VetBooks.ir 276 K. A. Moriello Fig. 12 Wood’s lamp positive hairs in the interdigital space. This lesion was not noticed during examination in room light training. Wood’s lamp can rapidly identify high risk cats. For example, in one shelter, 1226 cats were surrendered in a 7-month period [48]. Of these cats, 273 (22.3%) were culture positive, but only 60 of 273 were lesional, Wood’s lamp positive, and direct examination positive. The 213 remaining culture-positive cats were nonlesional and Wood’s lamp negative and were determined to be fomite carriers. The use of the Wood’s lamp at intake allowed for rapid identification of infected cats (50 of 60 being kittens). Box 2: Wood’s Lamp Practice Tips • • • • • • • • • • • Use a medical grade lamp with UV spectrum 320 to 400 nm wavelength Do not use hand-held battery-operated lamps Use a lamp with built-in magnification Lamps do not need to “warm up” Allow your eyes to light adapt to the dark Use a positive control slide Hold lamp close to skin (2–4 cm); minimizes false fluorescence Start at head and move slowly examining hair shafts Lift crusts and look for apple green fluorescing hair shafts Newly infected hairs are very short Worried about false fluorescence? Examine hair bulb irect Examination of Scales and Hairs D Direct examination is a POC diagnostic test that can confirm the presence of a dermatophyte infection at the time of initial presentation. Material can be collected with the aid of a dermoscope and Wood’s lamp or via a combination of skin scraping and plucking of hairs. A recent study showed that the best way to collect VetBooks.ir Dermatophytosis 277 Fig. 13 Direct examination of infected hair (original magnification 4×). Note that infected hairs are pale and wider than normal hairs which appear as 'threads' in comparison. specimens is via both superficial skin scraping and plucking of hairs from lesions. In cats, combined hair plucking and skin scraping of lesion margins confirmed the diagnosis in 87.5% of cases [49]. In this study, a Wood’s lamp was not used, and had it been, the results may have been higher. The authors used mineral oil for mounting of specimens and no clearing agent; clearing agents destroy fluorescence, cause artifacts, and damage microscope lens. The author routinely mounts specimens in mineral oil. This is a time and cost effective test to master as it allows for microscopic examination for mites with the same specimen. The most helpful aid in learning this technique is to have images comparing normal and abnormal hairs (Figs. 13, 14, and 15). Direct examination tips are summarized in Box 3. Box 3: Direct Examination Practice Tips Use a Wood’s lamp or dermoscope to help identify suspect hairs Collect samples by both plucking and scraping of the lesion Use a skin scraping spatula to scrape margins of lesions Mount specimens in mineral oil; do not use a clearing agent Use glass coverslips Abnormal hairs are easily visible at 4× and 10× Infected shafts are wider, paler, and often retractile compared to normal hairs Tips to find hairs • Use a picture guide that shows abnormal vs normal hairs • Hold a Wood’s lamp (2–3 cm) over the slide to help find the hairs • Add lactophenol cotton blue or new methylene blue to the mineral oil; let sample set for 10 to 15 minutes before examination; infected hairs will be blue tinged VetBooks.ir 278 K. A. Moriello Fig. 14 Direct examination of infected (short thick arrow) and uninfected hairs (long thin arrow) Fig. 15 Direct examination of infected hair in mineral oil and lactophenol cotton blue after 15 minutes Skin Cytology Macroconidia are never seen on cytological examination of skin cytology. However, M. canis arthrospores may be observed in cats with severe infections (Fig. 16). Fungal Culture Fungal cultures can be a POC or RL diagnostic test (see Box 5). If infection is confirmed via direct examination of hair and scale, fungal culture is used to confirm the dermatophyte species. Fungal culture can be used to confirm the diagnosis if POC diagnostics do not. A recent study revealed good correlation between point-of-care VetBooks.ir Dermatophytosis 279 Fig. 16 Cytologic examination of a skin cytology from a cat with dermatophytosis. Numerous arthroconidia are seen on the surface of the corneocyte cultures and reference laboratories when both gross colony formation along with microscopic features were used to identify colonies [50]. However, there was an almost 20% error rate when color change alone was used. The most commonly used POC fungal culture medium is Dermatophyte Test Medium (DTM) which consists of a nutrient medium plus inhibitors of bacterial and saprophytic growth and phenol red as a pH indicator. Several variants are available, some of which claim to speed growth of the culture, but a study found that all appeared to perform similarly [51]. From a practical perspective, use a POC plate with a large volume of medium; it is easy to inoculate with a toothbrush or hairs and is easily sampled for microscopic examination. The author discourages the use of DTM glass vials because they are hard to inoculate and sample. Vials that base their diagnostic value on “positive color change” are not recommended. Plates should be stored in individual plastic bags to prevent cross contamination and protect against desiccation and media mite infestation. The author stores samples in a plastic container and monitors temperature using an inexpensive digital thermometer for fish tanks. Dermatophyte colonies may appear as soon as 5 to 7 days after inoculation. Plates should be inspected daily for growth by holding the plate up to the light to look for colony growth (Fig. 17). To minimize contaminant growth, do not open plates until there is adequate growth to sample. It is common to see early colony growth using this backlighting technique several days before a red color change develops around the colony. The red color change is caused by a change in the pH of the medium and is not diagnostic: it merely identifies colonies for microscopic sampling (Fig. 17). The color change usually occurs at the time the colony is first visible, but may develop within 12 to 24 hours after visible fungal growth. All fungal growth, including non-pathogens, will eventually produce a red media color change after the colony has grown for several days to a week. Dermatophyte colonies are never green, gray, brown, or black. Pathogens are pale or buff in color and have a powdery to cottony mycelial growth. All suspect colonies should be examined microscopically (Figs. 18 and 19). VetBooks.ir 280 Fig. 17 DTM plate with initial growth of M. canis. Around the small white cottony colonies, the culture media color turned red. Note: Gloves should be worn when handling fungal culture plates. (Courtesy of Dr. Chiara Noli) Fig. 18 Microscopic example of M. canis from a clear acetate tape preparation. The sample was allowed to stand for 15 min before examination, making macroconidia more visible. Note the tapered ends, rough surface, and thick walls Fig. 19 High power (100×) of M. canis macroconidia. Note the thick walls as the most consistent feature K. A. Moriello VetBooks.ir Dermatophytosis 281 Unless there is a sampling error such as plucking only a few hairs rather than using a toothbrush for sampling lesions, large numbers of colonies of the dermatophyte will appear on the plate if the animal is truly infected. The number of colonies decreases as the infection resolves spontaneously or from treatment. One of the most common problems with in-house culturing is the lack of sporulation or growth, or both, of M. canis on DTM. A common cause of this is overinoculation of the fungal culture plates. This is characterized by rapid swarming of the plate with fluffy colony growth, but only unsporulated hyphae are noted on microscopic examination. This can be avoided by limiting the number of toothbrush inoculations on the plate to six to eight stabs; individual impressions should be clearly visible. A common question is how long to hold fungal culture plates. Recent research has shown that in cultures of human dermatophyte infections, 98.5% of fungal cultures were positive before day 17 [52]. A retrospective study of 2876 M. canis positive fungal cultures found that 98.2% were confirmed within 14 days of incubation [53]. The revised commendation is to consider a fungal culture negative if no pathogen or no growth has been isolated by day 14. Reference Laboratory Diagnostics PCR There is increasing interest and use of PCR in animals to diagnose dermatophytosis. This is because PCR is commonly used to diagnose dermatophytosis of nail in people because of the difficulty in isolation of pathogens via fungal culture. Routine bathing and use of over-the-counter topical antifungal preparations make isolation of human Trichophyton infections via fungal culture challenging. If the reference laboratory has the protocol, PCR on tissue can be used to aid in the diagnosis of deep dermatophyte infections in cats [54, 55]. Commercial reference laboratories are increasingly offering PCR as a diagnostic test. The major advantage of this test over fungal culture is the rapid turnaround time. It is important to remember that PCR is very sensitive and will detect both viable and non-viable fungal DNA. In addition, like toothbrush fungal cultures, PCR cannot differentiate between fomite carriage and true disease. Field studies using a commercial PCR test in cats from animal shelters found that the test has high sensitivity and high specificity [56, 57]. Samples can be collected using the toothbrush technique, but it is important to sample only the target lesion ensuring an adequate amount of follicular hair is collected for analysis. Alternatively, avulsed crusts with hair shafts and hair bulbs can be collected and submitted for examination. In one field study, the qPCR assay for Microsporum spp. was more useful for initial disease confirmation, while the qPCR M. canis assay was more useful for determining mycological cure [57]. When using this test to monitor for mycological cure, it may be helpful to bathe and dry the cat’s hair coat prior to sampling to minimize a positive PCR test from detection of non-viable DNA. VetBooks.ir 282 K. A. Moriello Histopathology There are two clinical presentations when histological examination of tissue is helpful to diagnose dermatophytosis. The first is when cats present with unusual skin lesions and routine point-of-care diagnostics do not identify a cause. Some cats with dermatophytosis will develop lesions that look clinically similar to pemphigus foliaceus. The second is the investigation of non-healing wounds or nodules caused by dermatophytosis (dermatophytic mycetoma or pseudomycetoma). It is important to remember to submit as large a section of tissue as possible because processing can result in marked shrinkage of the specimen [58]. The author routinely samples nodules via excisional biopsy or with a 6 to 8 mm skin biopsy punch. It is important to tell the pathology laboratory that dermatophytosis is suspected because routine stains (i.e., hematoxylin and eosin) are not as sensitive as periodic acid-Schiff (PAS) or Gomori’s methenamine silver (GMS) for detecting fungal elements in tissue. In addition, tissue (4–6-mm punch or wedge) should be submitted to a reference laboratory for fungal culture. Treatment Dermatophytosis is a self-limiting disease in otherwise healthy animals. Treatment is recommended to shorten the course of the infection because it is infectious and contagious. Treatment is summarized in Table 1. Confinement Considerations Confinement needs to be reconsidered in the treatment of this disease. The recent treatment consensus guidelines state that “Confinement needs to be used with care and for the shortest time possible. Dermatophytosis is a curable disease, but behavior problems and socialization problems can be life-long if the young or newly adopted animals are not socialized properly.” [2] This disease is most common in kittens at the same time that it is critical for socialization and bonding. Veterinarians need to consider animal welfare and quality of life when making a recommendation for confinement. The purpose of confinement is to limit the amount of work needed to do routine cleaning. The living area should allow for 24/7 exercise, normal behavior (i.e., play and jumping), sleeping, eating, and socialization. It is important to remember that disease transmission is limited via the use of concurrent systemic antifungal therapy and, most importantly, topical therapy. Infection from contaminated environments is an inefficient and rare mode of transmission. The infection is transmitted by direct contact with spores on the hair coat. Topical therapy and simple barrier protection (i.e., gloves and long shirt sleeves) and reasonable human behavior (i.e., not “wearing the kitten/cat”) will minimize the risk of transmission to people. Dermatophytosis 283 VetBooks.ir Table 1 Quick summary of treatment recommendations Confinement Limit confinement to easily cleaned room. Kitten/cat must have 24/7 access to freely move and exercise Human interaction and socialization must be possible Topical therapy Twice weekly whole body therapy with lime sulfur or enilconazole rinses or shampoo therapy with a miconazole-ketoconazole-climbazole/chlorhexidine shampoo Daily focal miconazole 2% vaginal cream for lesions on the face Daily otic medicaments that do not contain antibiotics for lesions in/on ears Systemic therapy Oral itraconazole 5 mg/kg orally once daily on a week on/week off basis: Do not use compounded or reformulated itraconazole Terbinafine 30 to 40 mg/kg orally once daily is an option if itraconazole is not available Do not use lufenuron, griseofulvin, or fluconazole Cleaning “Clean as if company is coming twice weekly” Keep cat hair to a minimum and use disinfectant wipes between “cleanings” Hard surfaces Focus on removal of cat hair and debris, wash with a detergent until visibly clean, rinse and remove excess water, and use ready-to-use disinfectants labelled as effective against Trichophyton spp. (i.e., bathroom cleaners) Bleach is no longer recommended Soft surfaces Wash laundry twice to disinfect; do not over-stuff the washer tub and use the longest cycle available Vacuum carpets to remove cat hair; disinfect with steam cleaning or washing twice with a beater brush carpet shampooer Monitoring Start monitoring after a cat/kitten is lesion-free and there are no fluorescing hair shafts One fungal culture is compatible with mycological cure in most cats, two may be needed in complicated situations, PCR can be used but may be associated with false positives Clipping of the Hair Coat There are no controlled studies comparing the number of days to cure in cats that have been clipped to those that have not been clipped. Based upon treatment outcomes in dedicated dermatophyte treatment programs in the United States, it is the author’s experience that routine clipping of the hair coat is not necessary. Clipping of the hair coat requires sedation and can result in thermal burns which may not be clinically apparent until weeks later. Based upon experimental treatment studies, clipping of the hair coat can temporarily worsen lesions and/or result in the development of satellite lesions [30, 31]. If lesions or hair mats need to be removed, use children’s round tipped metal scissors. Place the cat on newspaper to allow for easy disposal of infective material. If long haired cats are slow to cure and/or the owner VetBooks.ir 284 K. A. Moriello cannot thoroughly soak the hair coat, scissor clipping to facilitate the penetration of topical antifungal treatment may be helpful. What is helpful is to brush the hair coat prior to the application of topical therapy to remove broken and easily shed hairs. Plastic flea combs are ideal for this purpose. Topical Therapy Topical therapy is as important as systemic antifungal therapy in the treatment of feline dermatophytosis. Systemic antifungal therapy eradicates infection within the hair follicle but does not kill infective spores on or in the hair shaft or on the hair coat. Topical therapy protects against disease transmission. Topical therapy minimizes shedding of infective spores into the environment which greatly decreases, if not prevents, the potential of positive fungal cultures due to fomite contamination [59, 60]. Concurrent topical therapy will decrease the overall length of treatment. It is important to remember that until the infection is eradicated within the hair follicle, the hair coat will be continually reseeded with infective spores. Twice weekly whole body rinses or shampoos are recommended for the duration of treatment. Exposed uninfected cats and dogs should be treated with a whole body antifungal rinse or shampoo to minimize risk of transmission. The most consistently effective antifungal products in vivo studies are lime sulfur, enilconazole, or miconazole/chlorhexidine shampoos [60–66]. These products are fungicidal. The author has also successfully used combination miconazole/ chlorhexidine and climbazole/chlorhexidine leave-on mousse formulations in cats that could not be wetted (i.e., cats with bandages, upper respiratory infections). In vitro studies have shown that antifungal shampoos containing miconazole, ketoconazole, climbazole, or accelerated hydrogen peroxide are antifungal when used with a minimum of a 3-minute contact time [67]. There is strong evidence from in vitro and in vivo studies on the antifungal activities of essential oil preparations as options [59, 68, 69]. Based upon treatment of cats in dermatophyte treatment centers, the most common reason for failure to cure is the presence of infective hairs in hard to treat areas. People are reluctant to apply antifungal rinses or shampoo to the face and in/near the ears of cats. Unfortunately, these are the sites of infective hairs when “failure to cure” cats are examined with a Wood’s lamp. The author recommends the daily use of miconazole 2% vaginal cream on the face and periocular area if lesions are found. This particular product is used to treat fungal keratitis and is safe [70]. For infective hairs in the ears, antifungal otic products (chlorhexidine/miconazole or chlorhexidine/ketoconazole, or clotrimazole) can be used daily. Dermatophytosis 285 VetBooks.ir Systemic Antifungal Therapy Systemic antifungal therapy eradicates the infection within the hair follicle and is used with concurrent topical therapy. Unless there is a contraindication, it is indicated in all cats with dermatophytosis. The antifungal drug of choice for cats is itraconazole (Itrafungol, Elanco Animal Health). It is labelled for use at 5 mg/kg orally once daily on an alternating week on/ week off treatment schedule. An initial treatment schedule of 3 cycles is recommended, but additional cycles may be needed in some cats that have not reached mycological cure by 6 weeks [71]. Itraconazole accumulates in adipose tissue, sebaceous glands, and hair for weeks after administration, making it suitable for pulse therapy protocols [72]. Itraconazole has no age or weight limitations. Kittens as young as 10 days of age were treated with 5 mg/kg orally for four consecutive weeks, and no treatmentrelated side effects were reported [72]. The drug is well tolerated, and no treatment studies have reported death or adverse effects that required discontinuation of the drug when used at doses for treatment of feline dermatophytosis [2]. Side effects were rare and included salivation, mild anorexia, and vomiting [2, 71] Deaths associated with its use have not been reported. Target animal safety studies in which cats were given 5, 15, and 25 mg/kg itraconazole for 7 days on alternate days for 17 weeks with an 8-week recovery period noted dose-related hypersalivation, vomiting, and loose stool which were mild to moderate and self-resolving [73]. Elevations in hepatic enzymes above baseline were sporadic, dose-related, and rarely above laboratory normal ranges. In an extensive review of the literature, reports of severe adverse effects of itraconazole in cats were all traced to studies or case series treating cats with high doses for long periods of time [2]. The author is aware of many anecdotal reports of “itraconazole resistance,” and, when investigated, compounded itraconazole was used. A recent paper compared the reference capsule, reference solution, compounded capsule, and compounded suspension in a randomized cross-over study [74]. The findings revealed that compounded formulations were poorly and inconsistently absorbed. Compounded itraconazole should not be used. Terbinafine has been used successfully for the treatment of M. canis dermatophytosis [2]. Studies have shown that terbinafine is highly concentrated in the hair coat of cats after 14 days of continuous administration and is suitable for pulse therapy [75]. Doses in the literature range from 5 to 40 mg/kg per day; however, higher doses of 30–40 mg have been reported to be clinically more effective. The most common side effects are vomiting, diarrhea, and soft stools. Griseofulvin was the first oral antifungal used to treat feline dermatophytosis, but it is no longer recommended given the superior efficacy of itraconazole and terbinafine. It is also a known teratogen and can cause dose-unrelated idiosyncratic bone marrow VetBooks.ir 286 K. A. Moriello suppression. Ketoconazole is effective against dermatophytes but is poorly tolerated in cats and should not be used. Fluconazole has poor efficacy against dermatophytes and should not be used. Numerous well-controlled studies have shown that lufenuron has no efficacy and should not be used to treat dermatophytosis [32, 33, 76]. Fungal Vaccines Antifungal vaccines for M. canis have shown no efficacy against challenge exposure but may be useful as adjuvant therapy. Commercial vaccines are limited in availability [2]. Disinfection of the Environment The primary reason to disinfect the environment is to minimize fomite contamination of the hair coat which will make it difficult to determine mycological cure. Fomite contamination can lead to over-treatment of cats, over-confinement, expense, and in some cases euthanasia. Review of the literature found that contact with a contaminated environment alone in the absence of concurrent micro-trauma is a rare source of infection for people and cats [2]. Severely contaminated environments, e.g., hoarding situations, are a risk factor for cats under severe physiological stress or predisposed to skin micro-trauma (e.g., flea infestation). Evidence-based studies on environmental decontamination have now shown that it is much easier to decontaminate an environment than past literature suggests and/ or what clients may find on Internet resources. Dermatophyte spores can only live and reproduce in keratin; they do not multiply or invade the environment as many clients believe. It is important to stress to clients that dermatophyte spores are not like mildew or mold that overgrows in homes after water damage. Clients will report reading that “ringworm lives” in the environment up to 24 months. This comment stems from a laboratory study where specimens (n = 25 total) were stored and sampled at various time points. In that study, three of six specimens stored between 13 and 24 months were viable on fungal culture medium [77]. This study did not document that stored specimens were able to cause disease. In a different study, stored specimens were only viable for 13 months, and it was not possible to induce infection in kittens [78]. In the author’s experience with stored specimens for 25 years, isolates loose viability and become culture negative within months. In one experiment, 30% (45 of 150 specimens) were culture negative within 5 months, and all were culture negative by 9 months. Finally, spores in infective hairs and scales are very susceptible to moisture: 100 specimens were culture negative after being exposed to high humidity for 3 days. Box 4 summarizes environmental cleaning recommendations. The environmental cleaning focus needs to be on mechanical cleaning and removal of debris coupled with washing of the target surface until visibly clean. The surface needs to be rinsed of detergent as this will inactivate many disinfectants. In addition, the surface needs to be free of any excess water as this will dilute disinfectants. A recent study VetBooks.ir Dermatophytosis 287 showed that household bathroom cleaners labelled as efficacious against Trichophyton spp. are effective against the naturally infective form of M. canis and Trichophyton spp. [79] Clients should be strongly advised against the use of household bleach as a disinfectant due its lack of detergency, lack of penetration into organic material, and human/animal health hazard. Box 4: Summary of Disinfection Recommendations Key points to stress: Spores do not multiply in the environment, spores do not invade surfaces like mildew or black mold, spores are easily removed via cleaning, and spores are susceptible to moisture, i.e., they die quickly post exposure. Key cleaning points: “If you can wash it, you can decontaminate it” and “clean as if company is coming.” Cleaning specifics: • Laundry: Wash twice in the washer on hot or cold water; bleach is not necessary. • Rugs: Keep pets off rugs and/or vacuum daily. Can be disinfected using “steam cleaning” or washing twice with a beater brush carpet scrubber. • Keep pets in easily cleaned rooms, but do not over-confine. Close closets and drawers, and remove knick-knacks. Remove debris and pet hair daily using dusting cloths or 3 M Easy Trap dust cloth (these are sticky “swiffers”) and then mop floors with a flat mop. Repeat two to three times weekly. • Disinfectants do not take the place of mechanical cleaning and washing; spores are like dust and are easily removed via mechanical cleaning. • Mechanical cleaning is most important, remove debris, wash with a detergent cleaner, rinse, and remove excess water. This alone can decontaminate surface. • Disinfectants are needed for spores not removed by cleaning. For safety, only use ready-to-use commercial disinfectants labelled as efficacious against Trichophyton spp., thoroughly wet target non-porous surfaces, and let dry. • Clean transport cages. • Environmental sampling is NOT cost-effective and not recommended unless there is concern about fomite contamination. Clients often ask what they can do to minimize environmental contamination in addition to cleaning. In addition to systemic antifungal therapy, the most important thing is to use topical antifungal therapy to disinfect the hair coat. In a recent study, proper cleaning combined with topical therapy resulted in homes being free of infective material within 1 week of starting treatment and remaining so throughout the study [69]. In a study of 70 homes contaminated by M. canis infected cats, only 3 of 69 homes needed more than one cleaning for complete decontamination. One home was never decontaminated due to admitted owner non-compliance [80]. 288 K. A. Moriello VetBooks.ir Monitoring and Endpoint of Treatment Mycological Cure The term “mycological cure” was introduced into to the veterinary literature in 1959 and was defined as two negative fungal cultures at 2 weeks apart in a study using griseofulvin to treat long haired cats with M. canis feline dermatophytosis [81]. Because this is a contagious and infectious disease, M. canis is not part of the normal fungal flora of cats, and the disease is of zoonotic importance, it is reasonable to treat cats until the infectious agent is no longer detectable via fungal culture(preferred) or PCR. A recent study has found that the first negative fungal culture was predictive of mycological cure in >90% of cats that were otherwise healthy, where there was good compliance with cleaning, and topical and systemic treatment [82]. Treatment Length A common question from owners is “how long until the cat is cured”? The response “as long as it takes” or “until mycological cure” is true, but irritating to owners. In a recent placebo controlled study using itraconazole at current label recommendations, lesion resolution, Wood’s lamp examinations, and weekly fungal cultures were performed for 9 weeks [71]. In this study, cats did not receive any topical therapy. Mycological cure was documented as early as week four of treatment. At week nine, 39 of 40 (97.5%) cats had Wood’s negative examinations. By the end of 9 weeks, 36 of 40 (90%) cats had at least 1 negative fungal culture, and 24 of 40 had two negative fungal cultures. These cats did not receive topical therapy. In a shelter study using 21 days of consecutive itraconazole and concurrent topical twice weekly lime sulfur, the mean number of days to mycological cure was 18 (range 10–49 days) in a group of 90 cats that were otherwise healthy [62]. In a later study involving random source cats with a multitude of concurrent illnesses, the mean number of days to cure was 37 days (range 10–93) [83]. Based upon these studies, it is reasonable to answer the question as follows: in otherwise healthy cats receiving itraconazole and topical therapy, mycological cure can be expected within 4 to 8 weeks. If the cat has concurrent illnesses, e.g., upper respiratory infection or poor nutrition, treatment will be longer. Recommended Monitoring Clinical Cure It is well established that clinical cure precedes mycological cure. There should be resolution of clinical signs, and clients are usually capable of these observations. A lack of resolution and/or development of new lesions indicate a treatment problem or misdiagnosis. In the author’s experience, cats receiving itraconazole show rapid resolution of clinical signs. VetBooks.ir Dermatophytosis 289 ood’s Lamp Examination W It is now known that Wood’s lamp examinations are very useful for both detection of M. canis-infected hairs and for monitoring of infections. This tool is strongly recommended to monitor infections provided the user has a proper Wood’s lamp, cats can be handled, and the room darkened. As the infection is eradicated in the hair follicle, fluorescence disappears from the proximal portion of the hair shaft (i.e., intra-follicular portion). As a new healthy hair grows, there is less and less fluorescence on the hair shaft. Residual pigment on the hair tips is common in cats that have recovered from dermatophytosis and reflects residual pigment deposited in the hair shaft at the time of initial infection. PCR Testing Commercial PCR testing for mycological cure can be used provided there is high confidence in the reference laboratory performing the test. It is important to remember that PCR will detect both viable and non-viable fungal DNA. Leave-on rinses or mousses will kill fungal spores, but because these are not “rinsed” off the hair coat, non-viable fungal DNA may be present. Fungal PCR testing should be considered only after there is clinical cure and lack of Wood’s lamp hair shaft fluorescence, routine cleaning is in place, and only if topical therapy has been used concurrently with systemic antifungal therapy. If a leave-on antifungal has been used for topical therapy, wash the cat to remove any residual fungal DNA. qPCR M. canis assay was found to be more useful for detecting mycological cure than the qPCR Microsporum assay [57]. The use of cycle thresholds was found not to be helpful for determining mycological cure [84]. Fungal Culture The most commonly used diagnostic test to determine mycological cure in cats is a toothbrush fungal culture. There is no established “best practice” for when to start monitoring response to treatment using toothbrush fungal cultures. What is important to note is that it is no longer acceptable to report fungal culture results as “positive” or “negative.” The number of dermatophyte colony-forming units (cfu) per plate provides valuable information (Boxes 5 and 6). Clinical examination, fungal culture findings, and Wood’s lamp examination are used to determine if a cat is infected or cured. • Do weekly fungal cultures once the decision has been made to start evaluating for mycological cure. • Fungal culture plates do not need to be held longer than 14 days; culture negative plates at day 14 should be considered negative. • Do in-house cultures or use a reference laboratory that is familiar with the toothbrush inoculation technique and will provide weekly updates on cfu/plate. • See Box 6 for use of cfu/plate and in practice. • Continue topical therapy until the cat is mycologically cured (negative PCR or at least one negative toothbrush fungal culture). VetBooks.ir 290 K. A. Moriello Box 5: Fungal Culture Practice Tips and Use of Colony-Forming Units Fungal culture plates • Use large volume easy open plates. • Do not over-inoculate plates; make sure bristles show a pattern on surface. • Incubate in house in plastic bag to prevent cross contamination and minimize desiccation. • Incubate at 25 °C to 30 °C. • Examine daily for growth; use backlighting technique. • No growth plates can be finalized at 14 days; not necessary to hold for 21 days. Record growth twice weekly • NG – no growth. • C– contaminant growth bacterial or fungal. • S – suspect growth (early growth of a pale colony or early growth of pale colony with a red color change. • Pathogen – requires microscopic identification. In animals under treatment, the red color change may lag behind the growth of the pale colony especially as the animal approaches cure. Count colony-forming units (only with toothbrush culture technique) • The number of colony-forming units per plate can be used to monitor response to therapy. P or “pathogen score” is the nickname used for this system. –– P3-≥ 10 cfu/plate (often too many to count!) – indicates high risk cat and active infection –– P2 5–9/cfu plate – indicates need to continue treatment –– P1 1–4 cfu/plate – most consistent with fomite exposure or exposure to another infected animal; continue topical therapy; improve cleaning of environment; consider if there is exposure to infected animal Note: This system makes it easy to monitor culture results and provides a visual record of the pet’s response to treatment. In most cases, animals with severe infections will have a starting culture score of P3. As treatment progresses, the P score becomes lower. Cured animals have cultures with no growth or just contaminant on culture. The scoring system is also very helpful in identifying pets undergoing treatment that are exposed to fomite contamination. These animals commonly will have cultures fluctuating from negative to P1. When this pattern is seen, the owner can be instructed to improve hygiene in the home. As fomite contamination is removed, the fungal cultures become negative. In addition to identification of fomite exposure, this system also rapidly alerts the clinician to animals that are failing therapy or are VetBooks.ir Dermatophytosis 291 relapsing for one reason or another. Lack of response to therapy will be suggested by a persistently high P score. Relapses will be represented by a sudden increase in colony-forming units. Box 6: Interpretation of P-score, Lesions, and Wood’s Lamp Findings in Diagnosis and Treatment of M. canis Infections∗ P-score P3 (>10 cfu/ plate) P2 (5–9 cfu/ plate) P1 (1–4 cfu/ plate) Wood’s lamp Wood’s examination examination Examination of hair shafts of hair tips Interpretation Plan Lesional/ nonlesional Positive/ negative Positive/ negative High risk/not cured Treat or continue treatment Lesional Positive/ negative Positive/ negative High risk/not cured Nonlesional Positive Positive/ negative High risk/not cured Nonlesional Negative Positive/ negative Cured/low risk Lesional Positive/ negative Positive/ negative High risk/not cured Nonlesional Positive Positive/ negative High risk/not cured Nonlesional Negative Positive/ negative (glowing tips are common in cured animals) Cured/low risk Treat or continue treatment Treat or continue treatment Re-examine, apply whole body antifungal treatment, then repeat culture when dry Treat or continue treatment Treat or continue treatment Re-examine, apply whole body antifungal treatment, then repeat culture when dry Comments A single infected hair can produce a P3 culture, examine carefully Likely represents a “dust mop” scenario If “dust mop” cat, repeat culture will be negative Note cfu colony forming unit; “dust mop” refers to a cat that is mechanically carrying spores from environmental contamination ∗ Adapted from the treatment and monitoring procedures used in the Felines In Treatment Program at the Dane County Humane Society, Madison, Wisconsin, USA Reprinted with permission from [2] 292 K. A. Moriello VetBooks.ir Public Health Aspects Dermatophytosis was a disease of major public health concern because until relatively recently, there was no effective and safe antifungal treatment. Animalassociated infections were common because of people’s close association with agriculture and the lack of veterinary care for skin diseases of pet animals. The development of oral griseofulvin for use in people and small animals in the late 1950s was a major therapeutic advance for people and animals. The development of ketoconazole, itraconazole, terbinafine and a wide range of topical antifungals were further major advances. Feline dermatophytosis is a pet-associated zoonosis, and it is a veterinarian’s responsibility to inform clients of this risk and provide accurate information about the disease. The reader is referred to the references for a detailed discussion [2]. Key aspects to communicate to clients are the following: • Dermatophytosis occurs in both animals and people. In people, it is commonly called “toe nail fungus” or athlete’s foot fungus. • It is the same disease, just a different pathogen. The primary pathogen of people is Trichophyton. • The disease causes skin lesions and is treatable and curable. • From cats, the disease is transmitted via direct contact with hair or skin lesions, and that is why topical therapy is so important. Topical therapy decreases the risk of disease transmission. • Use reasonable barrier protection, e.g., as you would in handling an animal with infectious diarrhea. • Risk of contracting the disease from the environment is low. • Dermatophytosis is a common skin disease in immunocompromised people; however, literature review found that these infections are resurgences of preexisting human dermatophyte infections [85]. Animal-associated dermatophytosis was rare. • The most common complication of M. canis infection in immunocompromised people was a prolonged treatment time [86]. References 1. Weitzman I, Summerbell RC. The dermatophytes. Clin Microbiol Rev. 1995;8:240–59. 2. Moriello KA, Coyner K, Paterson S, et al. Diagnosis and treatment of dermatophytosis in dogs and cats.: Clinical Consensus Guidelines of the World Association for Veterinary Dermatology. Vet Dermatol. 2017;28:266–e68. 3. Graser Y, Kuijpers AF, El Fari M, et al. Molecular and conventional taxonomy of the Microsporum canis complex. Med Mycol. 2000;38:143–53. 4. Hawksworth DL, Crous PW, Redhead SA, et al. The Amsterdam declaration on fungal nomenclature. IMA Fungus. 2011;2:105–12. 5. Moriello KA, DeBoer DJ. Fungal flora of the coat of pet cats. Am J Vet Res. 1991;52:602–6. VetBooks.ir Dermatophytosis 293 6. Moriello KA, Deboer DJ. Fungal flora of the haircoat of cats with and without dermatophytosis. J Med Vet Mycol. 1991;29:285–92. 7. Meason-Smith C, Diesel A, Patterson AP, et al. Characterization of the cutaneous mycobiota in healthy and allergic cats using next generation sequencing. Vet Dermatol. 2017;28:71–e17. 8. Scott DW, Miller WH, Erb HN. Feline dermatology at Cornell University: 1407 cases (1988– 2003). J Feline Med Surg. 2013;15:307–16. 9. Scott DW, Paradis M. A survey of canine and feline skin disorders seen in a university practice: Small Animal Clinic, University of Montreal, Saint-Hyacinthe, Quebec (1987–1988). Can Vet J. 1990;31:830. 10. Hill P, Lo A, Can Eden S, et al. Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animal general practice. Vet Rec. 2006;158:533–9. 11. O’Neill D, Church D, McGreevy P, et al. Prevalence of disorders recorded in cats attending primary-care veterinary practices in England. Vet J. 2014;202:286–91. 12. Hobi S, Linek M, Marignac G, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 13. Moriello K. Feline dermatophytosis: aspects pertinent to disease management in single and multiple cat situations. J Feline Med Surg. 2014;16:419–31. 14. Lewis DT, Foil CS, Hosgood G. Epidemiology and clinical features of dermatophytosis in dogs and cats at Louisiana State University: 1981–1990. Vet Dermatol. 1991;2:53–8. 15. Cafarchia C, Romito D, Sasanelli M, et al. The epidemiology of canine and feline dermatophytoses in southern Italy. Mycoses. 2004;47:508–13. 16. Mancianti F, Nardoni S, Cecchi S, et al. Dermatophytes isolated from symptomatic dogs and cats in Tuscany, Italy during a 15-year-period. Mycopathologia. 2002;156:13–8. 17. Debnath C, Mitra T, Kumar A, et al. Detection of dermatophytes in healthy companion dogs and cats in eastern India. Iran J Vet Res. 2016;17:20. 18. Seker E, Dogan N. Isolation of dermatophytes from dogs and cats with suspected dermatophytosis in Western Turkey. Prev Vet Med. 2011;98:46–51. 19. Newbury S, Moriello K, Coyner K, et al. Management of endemic Microsporum canis dermatophytosis in an open admission shelter: a field study. J Feline Med Surg. 2015;17:342–7. 20. Polak K, Levy J, Crawford P, et al. Infectious diseases in large-scale cat hoarding investigations. Vet J. 2014;201:189–95. 21. Moriello KA, Kunkle G, DeBoer DJ. Isolation of dermatophytes from the haircoats of stray cats from selected animal shelters in two different geographic regions in the United States. Vet Dermatol. 1994;5:57–62. 22. Sierra P, Guillot J, Jacob H, et al. Fungal flora on cutaneous and mucosal surfaces of cats infected with feline immunodeficiency virus or feline leukemia virus. Am J Vet Res. 2000;61:158–61. 23. Irwin KE, Beale KM, Fadok VA. Use of modified ciclosporin in the management of feline pemphigus foliaceus: a retrospective analysis. Vet Dermatol. 2012;23:403–e76. 24. Preziosi DE, Goldschmidt MH, Greek JS, et al. Feline pemphigus foliaceus: a retrospective analysis of 57 cases. Vet Dermatol. 2003;14:313–21. 25. Olivry T, Power H, Woo J, et al. Anti-isthmus autoimmunity in a novel feline acquired alopecia resembling pseudopelade of humans. Vet Dermatol. 2000;11:261–70. 26. Zurita J, Hay RJ. Adherence of dermatophyte microconidia and arthroconidia to human keratinocytes in vitro. J Invest Dermatol. 1987;89:529–34. 27. Vermout S, Tabart J, Baldo A, et al. Pathogenesis of dermatophytosis. Mycopathologia. 2008;166:267–75. 28. Baldo A, Monod M, Mathy A, et al. Mechanisms of skin adherence and invasion by dermatophytes. Mycoses. 2012;55:218–23. 29. DeBoer DJ, Moriello KA. Development of an experimental model of Microsporum canis infection in cats. Vet Microbiol. 1994;42:289–95. 30. DeBoer D, Moriello K. Inability of two topical treatments to influence the course of experimentally induced dermatophytosis in cats. J Am Vet Med Assoc. 1995;207:52–7. VetBooks.ir 294 K. A. Moriello 31. Moriello KA, DeBoer DJ. Efficacy of griseofulvin and itraconazole in the treatment of experimentally induced dermatophytosis in cats. J Am Vet Med Assoc. 1995;207:439–44. 32. Moriello KA, Deboer DJ, Schenker R, et al. Efficacy of pre-treatment with lufenuron for the prevention of Microsporum canis infection in a feline direct topical challenge model. Vet Dermatol. 2004;15:357–62. 33. DeBoer DJ, Moriello KA, Blum JL, et al. Effects of lufenuron treatment in cats on the establishment and course of Microsporum canis infection following exposure to infected cats. J Am Vet Med Assoc. 2003;222:1216–20. 34. DeBoer DJ, Moriello KA. Investigations of a killed dermatophyte cell-wall vaccine against infection with Microsporum canis in cats. Res Vet Sci. 1995;59:110–3. 35. Sparkes AH, Gruffydd-Jones TJ, Stokes CR. Acquired immunity in experimental feline Microsporum canis infection. Res Vet Sci. 1996;61:165–8. 36. DeBoer DJ, Moriello KA. Humoral and cellular immune responses to Microsporum canis in naturally occurring feline dermatophytosis. J Med Vet Mycol. 1993;31:121–32. 37. Moriello KA, DeBoer DJ, Greek J, et al. The prevalence of immediate and delayed type hypersensitivity reactions to Microsporum canis antigens in cats. J Feline Med Surg. 2003;5:161–6. 38. Frymus T, Gruffydd-Jones T, Pennisi MG, et al. Dermatophytosis in cats: ABCD guidelines on prevention and management. J Feline Med Surg. 2013;15:598–604. 39. Scarampella F, Zanna G, Peano A, et al. Dermoscopic features in 12 cats with dermatophytosis and in 12 cats with self-induced alopecia due to other causes: an observational descriptive study. Vet Dermatol. 2015;26:282–e63. 40. Dong C, Angus J, Scarampella F, et al. Evaluation of dermoscopy in the diagnosis of naturally occurring dermatophytosis in cats. Vet Dermatol. 2016;27:275–e65. 41. Asawanonda P, Taylor CR. Wood’s light in dermatology. Int J Dermatol. 1999;38:801–7. 42. Wolf FT. Chemical nature of the fluorescent pigment produced in Microsporum-infected hair. Nature. 1957;180:860–1. 43. Wolf FT, Jones EA, Nathan HA. Fluorescent pigment of Microsporum. Nature. 1958;182:475–6. 44. Foresman A, Blank F. The location of the fluorescent matter in microsporon infected hair. Mycopathol Mycol Appl. 1967;31:314–8. 45. Sparkes A, Gruffydd-Jones T, Shaw S, et al. Epidemiological and diagnostic features of canine and feline dermatophytosis in the United Kingdom from 1956 to 1991. Vet Rec. 1993;133:57–61. 46. Wright A. Ringworm in dogs and cats. J Small Anim Pract. 1989;30:242–9. 47. Kaplan W, Georg LK, Ajello L. Recent developments in animal ringworm and their public health implications. Ann N Y Acad Sci. 1958;70:636–49. 48. Newbury S, Moriello K, Coyner K, et al. Management of endemic Microsporum canis dermatophytosis in an open admission shelter: a field study. J Feline Med Surg. 2015;17:342–7. 49. Colombo S, Cornegliani L, Beccati M, et al. Comparison of two sampling methods for microscopic examination of hair shafts in feline and canine dermatophytosis. Vet (Cremona). 2010;24:27–33. 50. Kaufmann R, Blum SE, Elad D, et al. Comparison between point-of-care dermatophyte test medium and mycology laboratory culture for diagnosis of dermatophytosis in dogs and cats. Vet Dermatol. 2016;27:284–e68. 51. Moriello KA, Verbrugge MJ, Kesting RA. Effects of temperature variations and light exposure on the time to growth of dermatophytes using six different fungal culture media inoculated with laboratory strains and samples obtained from infected cats. J Feline Med Surg. 2010;12:988–90. 52. Rezusta A, Gilaberte Y, Vidal-García M, et al. Evaluation of incubation time for dermatophytes cultures. Mycoses. 2016;59:416–8. 53. Stuntebeck R, Moriello KA, Verbrugge M. Evaluation of incubation time for Microsporum canis dermatophyte cultures. J Feline Med Surg. 2018;20:997–1000. 54. Bernhardt A, von Bomhard W, Antweiler E, et al. Molecular identification of fungal pathogens in nodular skin lesions of cats. Med Mycol. 2015;53:132–44. VetBooks.ir Dermatophytosis 295 55. Nardoni S, Franceschi A, Mancianti F. Identification of Microsporum canis from dermatophytic pseudomycetoma in paraffin-embedded veterinary specimens using a common PCR protocol. Mycoses. 2007;50:215–7. 56. Jacobson LS, McIntyre L, Mykusz J. Comparison of real-time PCR with fungal culture for the diagnosis of Microsporum canis dermatophytosis in shelter cats: a field study. J Feline Med Surg. 2018;20:103–7. 57. Moriello KA, Leutenegger CM. Use of a commercial qPCR assay in 52 high risk shelter cats for disease identification of dermatophytosis and mycological cure. Vet Dermatol. 2018;29:66. 58. Reimer SB, Séguin B, DeCock HE, et al. Evaluation of the effect of routine histologic processing on the size of skin samples obtained from dogs. Am J Vet Res. 2005;66:500–5. 59. Nardoni S, Giovanelli S, Pistelli L, et al. In vitro activity of twenty commercially available, plant-derived essential oils against selected dermatophyte species. Nat Prod Commun. 2015;10:1473–8. 60. Paterson S. Miconazole/chlorhexidine shampoo as an adjunct to systemic therapy in controlling dermatophytosis in cats. J Small Anim Pract. 1999;40:163–6. 61. Moriello K, Coyner K, Trimmer A, et al. Treatment of shelter cats with oral terbinafine and concurrent lime sulphur rinses. Vet Dermatol. 2013;24:618–e150. 62. Newbury S, Moriello K, Verbrugge M, et al. Use of lime sulphur and itraconazole to treat shelter cats naturally infected with Microsporum canis in an annex facility: an open field trial. Vet Dermatol. 2007;18:324–31. 63. Carlotti DN, Guinot P, Meissonnier E, et al. Eradication of feline dermatophytosis in a shelter: a field study. Vet Dermatol. 2010;21:259–66. 64. Jaham CD, Page N, Lambert A, et al. Enilconazole emulsion in the treatment of dermatophytosis in Persian cats: tolerance and suitability. In: Kwochka KW, Willemse T, Von Tscharner C, editors. Advances in Veterinary Dermatology. Oxford: Butterworth Heinemann; 1998. p. 299–307. 65. Hnilica KA, Medleau L. Evaluation of topically applied enilconazole for the treatment of dermatophytosis in a Persian cattery. Vet Dermatol. 2002;13:23–8. 66. Guillot J, Malandain E, Jankowski F, et al. Evaluation of the efficacy of oral lufenuron combined with topical enilconazole for the management of dermatophytosis in catteries. Vet Rec. 2002;150:714–8. 67. Moriello KA. In vitro efficacy of shampoos containing miconazole, ketoconazole, climbazole or accelerated hydrogen peroxide against Microsporum canis and Trichophyton species. J Feline Med Surg. 2017;19:370–4. 68. Mugnaini L, Nardoni S, Pinto L, et al. In vitro and in vivo antifungal activity of some essential oils against feline isolates of Microsporum canis. J Mycol Med. 2012;22:179–84. 69. Nardoni S, Costanzo AG, Mugnaini L, et al. Open-field study comparing an essential oil-based shampoo with miconazole/chlorhexidine for haircoat disinfection in cats with spontaneous microsporiasis. J Feline Med Surg. 2017;19:697–701. 70. Gyanfosu L, Koffuor GA, Kyei S, et al. Efficacy and safety of extemporaneously prepared miconazole eye drops in Candida albicans-induced keratomycosis. Int Ophthalmol. 2018;38:2089–210. 71. Puls C, Johnson A, Young K, et al. Efficacy of itraconazole oral solution using an alternating- week pulse therapy regimen for treatment of cats with experimental Microsporum canis infection. J Feline Med Surg. 2018;20:869–74. 72. Vlaminck K, Engelen M. An overview of pharmacokinetic and pharmacodynamic studies in the development of itraconazole for feline Microsporum canis dermatophytosis. Adv Vet Dermatol. 2005;5:130–6. 73. Elanco US I. Itrafungol itraconazole oral solution in cats. Freedom of Information Summary NADA 141–474, November 2016. 74. Mawby DI, Whittemore JC, Fowler LE, et al. Comparison of absorption characteristics of oral reference and compounded itraconazole formulations in healthy cats. J Am Vet Med Assoc. 2018;252:195–200. 75. Foust AL, Marsella R, Akucewich LH, et al. Evaluation of persistence of terbinafine in the hair of normal cats after 14 days of daily therapy. Vet Dermatol. 2007;18:246–51. VetBooks.ir 296 K. A. Moriello 76. DeBoer D, Moriello K, Volk L, et al. Lufenuron does not augment effectiveness of terbinafine for treatment of Microsporum canis infections in a feline model. Adv Vet Dermatol. 2005;5:123–9. 77. Sparkes AH, Werrett G, Stokes CR, et al. Microsporum canis: Inapparent carriage by cats and the viability of arthrospores. J Small Anim Pract. 1994;35:397–401. 78. Keep JM. The viability of Microsporum canis on isolated cat hair. Aust Vet J. 1960;36:277–8. 79. Moriello KA, Kunder D, Hondzo H. Efficacy of eight commercial disinfectants against Microsporum canis and Trichophyton spp. infective spores on an experimentally contaminated textile surface. Vet Dermatol. 2013;24:621–e152. 80. Moriello KA. Decontamination of 70 foster family homes exposed to Microsporum canis infected cats: a retrospective study. Vet Dermatol. 2019;30:178–e55. https://doi.org/10.1111/vde.12722. 81. Kaplan W, Ajello L. Oral treatment of spontaneous ringworm in cats with griseofulvin. J Amer Vet Med Assoc. 1959;135:253–61. 82. Stuntebeck RL, Moriello KA. One vs two negative fungal cultures to confirm mycological cure in shelter cats treated for Microsporum canis dermatophytosis: a retrospective study. J Feline Med Surg. 2019. https://doi.org/10.1177/1098612X19858791. 83. Newbury S, Moriello KA, Kwochka KW, et al. Use of itraconazole and either lime sulphur or Malaseb Concentrate Rinse (R) to treat shelter cats naturally infected with Microsporum canis: an open field trial. Vet Dermatol. 2011; 22: 75–9. 84. Jacobson LS, McIntyre L, Mykusz J. Assessment of real-time PCR cycle threshold values in Microsporum canis culture-positive and culture-negative cats in an animal shelter: a field study. J Feline Med Surg. 2018;20:108–13. 85. Rouzaud C, Hay R, Chosidow O, et al. Severe dermatophytosis and acquired or innate immunodeficiency: a review. J Fungi. 2015;2:4. 86. Elad D. Immunocompromised patients and their pets: still best friends? Vet J. 2013;197:662–9. VetBooks.ir Deep Fungal Diseases Julie D. Lemetayer and Jane E. Sykes Abstract Deep mycotic infections are uncommon in cats. However, in endemic regions, cryptococcosis, sporotrichosis, and histoplasmosis occur regularly in immunocompetent cats. Cryptococcosis and sporotrichosis are more prevalent in cats than in dogs, and histoplasmosis is as prevalent or possibly slightly more prevalent in cats than in dogs. Blastomycosis and coccidioidomycosis are rare in cats, even in highly endemic areas. Sino-nasal and sino-orbital aspergillosis are also infrequent worldwide but interestingly, brachycephalic cats appear to be predisposed. Lastly, infections with saprophytic opportunistic fungi usually result from an accidental cutaneous inoculation in otherwise immune-competent cats and cause localized signs. Occasionally, however, disseminated infections can occur. Cats with systemic mycosis frequently have cutaneous manifestations. Reported cutaneous signs include multifocal ulcerated or nonulcerated cutaneous masses, subcutaneous masses, and draining abscesses, among others. The cutaneous signs are frequently associated with systemic signs of illness and/or other organ involvement, which should raise suspicion for fungal infection. The present chapter focus on the epidemiology, clinical signs, including cutaneous signs, diagnostic tests, and treatment of clinically important systemic fungal infections in cats. In addition, it reviews the antifungal drugs currently available for the treatment of these infections. J. D. Lemetayer (*) · J. E. Sykes Veterinary Medical Teaching Hospital, University of California, Davis, CA, USA e-mail: jesykes@ucdavis.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_14 297 298 J. D. Lemetayer and J. E. Sykes VetBooks.ir Introduction Deep mycotic infections are uncommon to rare in cats worldwide. A 1996 study estimated a prevalence of seven deep mycotic infections per 10,000 cats in the USA [1]. Indeed, cats are relatively resistant to fungal infections and the prevalence of most fungal infections is lower in cats than in dogs except for cryptococcosis and sporotrichosis. Cats also may be slightly more susceptible to histoplasmosis than dogs [2]. This chapter will focus on the epidemiology, clinical signs, diagnostic tests for, and treatment of, clinically important systemic fungal infections in cats. Box 1: Dimorphic Fungi • Cryptococcosis, caused by C. gattii and C. neoformans, is the most common fungal disease in cats worldwide. • Histoplasmosis is seen as frequently as or slightly more frequently in cats than in dogs in endemic regions • Cats are also more susceptible to sporotrichosis. • Blastomycosis and coccidioidomycosis are both infrequent in cats. • Most cats are immunocompetent. • Cutaneous signs are frequent in these dimorphic fungal diseases. • Fluconazole is the first line treatment for most cases of cryptococcosis, and itraconazole is used for resistant cases of cryptococcosis (mostly C. gattii infections) and infections with other dimorphic fungal organisms. • A combination with amphotericin B is recommended in severe cases. • A short course of anti-inflammatory dose of glucocorticoids is recommended for CNS cases and animals with severe pulmonary disease. Cryptococcosis Epidemiology The most common fungal infection in cats is cryptococcosis [1]. Cryptococcus spp. are dimorphic basidiomycetous fungi. Two main species cause cryptococcosis in cats: Cryptococcus neoformans and Cryptococcus gattii. Rarely, other species have been implicated. Cryptococcus magnus was isolated from a cat with otitis externa in Japan [3] and in a cat with a deep limb infection in Germany [4]. Cryptococcus albidus was isolated from a cat with disseminated cryptococcosis in Japan [5]. Two of these three cats were tested for feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) and were negative [4, 5], and no other apparent underlying immunocompromise was identified in the three cats. Cryptococcus neoformans is the most common species of Cryptococcus isolated worldwide and include two varieties: C. neoformans var. neoformans and VetBooks.ir Deep Fungal Diseases 299 C. neoformans var. grubii. Cryptococcus neoformans var. grubii accounts for the majority of cases in Australia [6]. Cryptococcus gattii is mostly found in the west coast of the United States and in British Columbia, Canada; in South America, southeast Asia (New Guinea, Thailand), and in parts of Africa and Australia. While C. neoformans is more common than C. gattii in Australia, rural cats in Australia and cats from Western Australia seem to be more commonly infected by C. gattii than by C. neoformans [6, 7]. Cryptococcus neoformans can be found in avian guano, especially pigeon faeces; but is also found in other sources including milk, fermenting fruit juices, air, dust and decaying vegetation [6]. C. gattii is often found in the hollows of trees, especially Eucalyptus trees, in Australia, but has been associated with other hardwood tree species in other geographic locations. Cryptococcus spp. have been divided into molecular types. Cryptococcus neoformans var. grubii isolates belong to molecular types VNI and VNII, whereas C. neoformans var. neoformans isolates belong to molecular type VNIV [7]. A hybrid variety of serotype AD has been classified as molecular type VNIII. C. gattii isolates are classified as VGI, VGII, VGIII, and VGIV. There is a proposal to rename Cryptococcus molecular types as separate species of Cryptococcus, which remains controversial. Clinical Features in Cats Siamese, Birman, Ragdoll, Abyssinian, and Himalayan breeds seem to be overrepresented in studies evaluating cats with cryptococcosis [1, 6, 8–10], although this was not found in a study from California [11]. A male predisposition has been identified in a few studies [10, 12] but not in others [6, 9, 11]. Having access to the outdoors is also likely a risk factor but cats kept strictly indoors can also be affected [8]. Cats of all age are affected, and FIV or FeLV status does not seem to be a risk factor [6]. The incubation period is variable and can range from months to many years in animals which were initially able to control the disease [13]. After inhalation of the fungus, many cats have upper respiratory involvement with chronic sneezing, nasal discharge and nasal deformation and/or deformations of the structures adjacent to the nasal cavities such as the sinuses (Fig. 1). Involvement of the nasal cavity has been reported in 43–90% of cases [1, 6, 12]. Infections also involve the retina, draining lymph nodes and the central nervous system (CNS). Clinical signs include enlarged mandibular lymph nodes, blindness, dilated and fixed pupils, slow pupillary light reflexes, lethargy, ataxia, behavioural changes and disorientation. Single or multifocal ulcerated or nonulcerated cutaneous masses were seen in 31% and 41% of cases in two studies [1, 12]. The masses can be firm or fluctuant, raised, dome-shaped and erythematous. They frequently ulcerate and may ooze a greyish gelatinous exudate [1]. Other cutaneous lesions include plaques, miliary papules, firm, dome-shaped, alopecic and erythematous papules or nodules [14]. Cutaneous lesions are usually an extension of a sino-nasal pathology. Involvement of the skin VetBooks.ir 300 J. D. Lemetayer and J. E. Sykes Fig. 1 Cat with nasal cryptococcosis caused by Cryptococcus gattii and subcutis in multiple sites suggests dissemination of the infection. Other uncommon locations include the lungs (2–12% of cases), [1, 6, 15] gingiva [15], salivary glands [6], middle ear [16], kidneys, periarticular subcutaneous tissues, footpads and bones [6]. Diagnostic Tests Changes on complete blood count (CBC), serum biochemistry and urinalysis are mild and non-specific. [17] A specific diagnosis of cryptococcosis can be obtained with antigen detection using latex agglutination assays on serum. The assay can also be used on pleural or peritoneal effusions, urine, and cerebrospinal fluid (CSF). The clinical sensitivity of the test on serum in cats ranges from 90% to 100% and specificity ranges from 97% to 100% [18]. The sensitivity appears to be lower in dogs. If the antigen test is negative, and cryptococcosis is still a possibility, tissue samples should be submitted for cytology, histology and culture [11]. When titres are <1:200, confirmatory tests are strongly recommended. Enzymelinked immunosorbent assays (ELISAs) are also under study but data are not currently available. VetBooks.ir Deep Fungal Diseases 301 Fig. 2 India ink negative stain highlighting the Cryptococcus polysaccharide capsule On cytology, cryptococcal yeasts are encapsulated, spherical to oval yeasts measuring 4–10 μm with narrow-based budding. The thick mucopolysaccharide capsule is a major virulence factor for the pathogen because it allows the organism to hide from the host immune system. It appears as a clear halo in stained smears and can be visualized using India ink negative stains (Fig. 2) [19]. However, the capsule can vary in size and in some patients the capsule can be thin [20] which can sometimes complicate the diagnosis. In these cases, there can be morphological overlaps between Histoplasma and Cryptococcus on cytology [20]. On histopathology, yeasts may be associated with well-ordered granulomas or pyogranulomas, sometimes with a background of a few eosinophils, lymphocytes and plasma cells. Lesions may also contain a large number of yeasts and only a mild degree of inflammation. This results in a “soap bubble” appearance on haematoxylin and eosin staining (H&E) [14] due to the organism’s thick, non-staining, capsule. Macroscopically, these lesions are gelatinous masses (cryptococcomas). In skin biopsies, numerous organisms are often present in the dermis, panniculus and subcutis [14] but occasionally, less typical lesions can complicate the diagnosis. For example, in a case series of four cats with cutaneous cryptococcosis, severe granulomatous to pyogranulomatous cutaneous lesions were reported with large numbers of eosinophils, but organisms could not be seen using H&E stain in three of the four cats, and the organisms were capsule deficient [14]. When yeasts are not seen using H&E stain, special stains such as Grocott’s methenamine silver (GMS), periodic acid–Schiff (PAS), Fontana-Masson stain, Ziehl–Neelsen stain or Mayer’s mucicarmine stains may help reveal organisms. Polymerase chain reaction (PCR) assays can also be applied to fresh biopsies or formalin-fixed paraffin-embedded tissues [14]. False-positive PCR results can VetBooks.ir 302 J. D. Lemetayer and J. E. Sykes occur from nasal tissues since subclinical nasal cavity colonization can occur, and therefore positive results should always be considered with the rest of the clinical picture [17]. Fresh tissue can also be submitted for fungal culture. Cryptococcus spp. grow on most laboratory media in 2 to 10 days. Because the organisms grow in culture as a yeast, rather than a mould, on routine fungal media they are less likely to represent a laboratory hazard than organisms that grow as moulds [17]. Treatment and Prognosis The triazoles are the first line therapy in the treatment of cryptococcosis and can be used as a monotherapy for mild to moderate cryptococcal infections. Fluconazole is often preferred to itraconazole because of its good penetration in the brain, eye, and urinary tract; lower cost; and minimal adverse effects. However, the development of fluconazole resistance has been reported during treatment [21, 22]. Resistance to fluconazole can be due to overexpression or a change in the copy number of ERG11, the gene encoding for the target enzyme 14-α-demethylase [21, 22]. Efflux of triazole drugs via multidrug efflux transporters (AFR1 for C. neoformans and PDR11 for C. gattii VGIII) has also been identified. Isolates that are resistant to fluconazole remain susceptible to itraconazole but may demonstrate moderate voriconazole resistance [23]. In severe cases such as those with CNS involvement, addition of amphotericin B to either fluconazole or itraconazole is recommended [24]. While the penetration of amphotericin B into the CNS and vitreous is poor, the blood-brain or blood-eye barrier is compromised at the beginning of treatment so a clinical response can still occur. Flucytosine can also be used in combination with amphotericin B because of the synergy between the two anti-fungal drugs and because of flucytosine’s good penetration in the CNS, however it may be cost prohibitive. See Tables 1 and 2 for more information regarding anti-fungal drugs in cats. A short course of prednisolone may improve outcome for cats with CNS infection because it decreases CNS inflammation at the beginning of anti-fungal treatment and may help limit neurological deterioration [25]. Typically, at least 6 to 8 months of treatment is necessary, and often treatment needs to be continued for years [17]. Serial monitoring of serum antigen titres should be used to evaluate treatment response as a decline in titre correlates with elimination of organisms [12]. Treatment should be continued until the titre is zero. Unfortunately, relapse can still occur after successful treatment and after titres have become negative, sometimes as long as 10 years after therapy is discontinued [24]. Prognosis is generally good, with the possible exception of cats with CNS infection [24, 25]. The prognosis may also depend on the Cryptococcus species and molecular type. For example, it is the authors’ experience that infections with C. gattii VGIII tend to be less likely to be cured than those with VGII. While FeLV likely has a negative impact on the treatment response, the effect of FIV status on outcome is not clear. Good response to treatment is often seen despite a positive FIV status but these cats may have more severe disease and/or may respond more slowly to treatment [9, 10, 26]. Decreased antifungal activity Clinical use Mechanism of action Dose (continued) Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole Inhibition of 14α-demethylase, a CYT P450-dependant fungal enzyme = accumulation of 14α-methylsterols and disruption of the fungal cell membrane Oral suspension: 30 mg/kg Not available 50 mg/cat PO q 25–50 mg/cat PO or IV 5 mg/kg PO q 12–24 h, 12–24 h q 12–24 h 100 mg capsule q 48 h [129] Possible dose: 12.5 mg/cat once then 15 mg/kg q 48 h, or 15 mg/kg once then PO every 72 hours (with or 3 mg/kg q 12–24 h with extreme caution as may be 5–7.5 mg/kg q 24 h [90, oral solution. Do not use 120, 132] compounded solutions [130] associated with severe toxicity) [131] Yeasts, dimorphic fungi, Yeasts, dimorphic fungi, Dimorphic fungi, Malassezia spp., Candida spp., most moulds, including most moulds especially Aspergillus spp. and some Dimorphic fungi Malassezia spp., zygomycosis Aspergillus spp. other moulds Coccidioides spp., Cryptococcus spp., Histoplasma spp. Sporothrix schenckii, Poor activity against Aspergillus spp. zygomycosis intrinsically resistant, many moulds, poor activity against including many moulds Aspergillus spp. Histoplasma: Development of resistance during treatment Table 1 Azole antifungal drugs used in cats VetBooks.ir Deep Fungal Diseases 303 Strong inducer CYT P450: many drug interactions Additional comments Itraconazole Good distribution into skin, bone & lungs. Limited penetration to CNS, eyes and kidneys/urine Reported in 25% of cases [134]. Gastrointestinal signs, hepatotoxicity and lethargy For the capsules: give with food and avoid antacid medications. Therapeutic drug monitoring at steady state (14-21d) [135] recommended Fluconazole Widely distributed including eyes, CNS and kidneys/urine [133] Well tolerated. Gastrointestinal signs, hepatotoxicity uncommon Very good oral absorption CNS central nervous system, CYT P450 cytochrome P 450, PO per os, h hours, d days Common: Gastrointestinal signs, hepatotoxicity Ketoconazole Good penetration into most tissues but not CNS Adverse effects Tissue distribution Table 1 (continued) Gastrointestinal signs and increased liver enzyme activities Visual changes (miosis), ataxia, paralysis, hypersalivation, hypokalaemia and arrhythmias [131] Give without food. Therapeutic drug monitoring recommended (trough concentration). Strong inducer CYT P450: many drug interactions Give with food and avoid antacid medications. Low oral absorption. Therapeutic drug monitoring recommended (trough concentration) Posaconazole Widely distributed but probably not in urine Voriconazole Widely distributed including eyes, CNS and kidneys/urine VetBooks.ir 304 J. D. Lemetayer and J. E. Sykes Decreased antifungal activity Tissue distribution Clinical use Doses Mechanism of action Some Aspergillus spp. Poor efficacy against Pythium insidiosum Poor penetration of the CNS & eyes. Liposomal and lipid complex formulations have better CNS penetration and less nephrotoxicity Amphotericin B Formation of pores in the fungal cell membrane by binding to sterols = leakage of ions Deoxycholate AmB: 0.25 mg/ kg IV or 0.5 mg/kg SC AmB lipid complex and liposomal AmB: 1 mg/kg IV 3 times weekly (up to 12 treatments) Yeasts, dimorphic fungi and most moulds Reported resistance for some dermatophytes [137] and Aspergillus spp. [138] Concentrate in skin nails and hairs Dermatophytes, maybe useful in combination with other antifungal drugs for various mould infections Terbinafine Inhibition of squalene epoxidase = reduction of ergosterol production in the fungal membrane 30–40 mg/kg PO q 24 h Table 2 Other clinically important anti-fungal drugs in cats (continued) Never used as sole agent because of rapid development of resistance Widely distributed including eyes, CNS Cryptococcus spp. and Candida spp. Invasive aspergillosis refractory to other antifungal therapy, invasive candidiasis. Some activity against Histoplasma spp. and Coccidioides spp. Variable activity against other filamentous fungi Cryptococcus spp., Fusarium spp., Rhizopus spp. and Mucor spp. are resistant [139] Widely distributed. Poor penetration of the CNS & eyes 1 mg/kg IV once then 0.75 mg/kg q 24 h [136] Flucytosine Deamination of flucytosine to 5-fluorouracil = interfere with DNA replication and protein synthesis 25–50 mg/kg PO q 6–8 h Caspofungin Inhibition of β-1,3-D- glucans = disturb the integrity of the fungal cell wall VetBooks.ir Deep Fungal Diseases 305 Amphotericin B Cumulative nephrotoxicity (mostly AmB deoxycholate), rarely haemolytic anaemia [140]. Sterile injection site abscesses with SC injections Liposomal and lipid complex formulations have better CNS penetration and less nephrotoxicity Low oral absorption [141] Terbinafine Well tolerated. Rarely, GI toxicity and facial pruritus Caspofungin Possible anaphylactic reaction. Transient fever and diarrhoea reported [136] AmB Amphotericin B, CNS central nervous system, GI gastro-intestinal, IV intravenous, PO per os, SC subcutaneous Additional comments Adverse effects Table 2 (continued) Avoid in animals with renal failure Flucytosine Myelosuppression and GI signs VetBooks.ir 306 J. D. Lemetayer and J. E. Sykes Deep Fungal Diseases 307 VetBooks.ir Histoplasmosis Epidemiology Histoplasma capsulatum is a dimorphic, soil-borne fungus that is endemic in the USA (especially in the central and eastern states but has also been described in California and Colorado), Central and South America, Africa, India and Southeast Asia [27, 28]. It is found worldwide in various mammalian species but besides cases in these endemic areas, cases of histoplasmosis in cats have only been described in Ontario, Canada [29], Thailand [30] and Europe (Italy, Switzerland) [28, 31]. In a 1996 study, histoplasmosis was the second most common fungal disease in cats in the USA with an incidence of 0.01% of the total feline hospital population of the veterinary medical database [1]. Histoplasma capsulatum has been divided into eight to nine geographic clades by multi-locus sequence typing: North American-1, with possibly a related phylogenetically distinct strain isolated from non-endemic American areas; North American-2; Latin American group A; Latin American group B; Australian; Netherlands (of Indonesian origin); Eurasian; and African [32]. The primary reservoir of H. capsulatum is the intestinal tracts and guano of bats. It can also be found in decaying avian guano (especially around blackbird or starling roosts and chicken coops). After inhalation or ingestion, the fungus transforms into a yeast phase within the body of cats and is engulfed by phagocytic cells, primarily macrophages. Trafficking of these cells results in dissemination of the yeasts via the blood and lymphatics away from the lung and gastrointestinal tract to organs of the mononuclear phagocyte system mostly (lymph nodes, liver, spleen, and bone marrow) as well as other tissues. Yeast are 2–4 μm in diameter and are surrounded by a 4 μm thick wall and reside within mononuclear phagocytes [33]. Clinical Features in Cats Cats of all age can be affected with a mean age, of 4 and 9 years in two studies [1, 34]. Persian cats may be slightly over-represented [1]. A sex predisposition has not been clearly identified, but females were over-represented in one case series [34]. Most cats are not concurrently infected with either FeLV or FIV. The disease seems to be diagnosed more often between the months of January to April [1] and can also affect cats that are housed exclusively indoors [35]. The reported duration of clinical signs before diagnosis of histoplasmosis ranged from 2 weeks to 3 months. [1] When cats have clinical histoplasmosis, disseminated disease is the most commonly reported clinical presentation [36]. Clinical signs exhibited by cats with disseminated disease are mostly non-specific and include lethargy, weight loss, fever, anaemia, dehydration, weakness and anorexia [1, 34]. Respiratory signs such as dyspnoea and tachypnoea are common, but cough is rare. Other common clinical signs include hepatomegaly, icterus, lymphadenopathy and splenomegaly [36, 37], ocular signs (chorioretinitis, anterior uveitis, or retinal detachments) [1, 29, VetBooks.ir 308 J. D. Lemetayer and J. E. Sykes 38] and skeletal involvement (lameness or swelling of one or more limbs) [1, 38, 39]. Clinical signs of gastrointestinal tract involvement such as vomiting, diarrhoea, melaena or haematochezia are less common than in dogs [2]. Less common sites of infection include the skin [28, 38, 40, 41], CNS [42], oral mucosa [43] and urinary bladder [44]. Cutaneous signs consist usually of multiple papules and nodules which may be ulcerated and exude serosanguineous fluid. A case of cutaneous fragility secondary to disseminated histoplasmosis has also been described [41]. The cat had a large skin tear that developed over the dorsal cervical region with epidermal atrophy, dermal collagen separation, and infiltration in the dermis and subcutis with macrophages and intravascular monocytes containing Histoplasma yeasts on histology. Diagnostic Tests CBC findings include anaemia, which is often normocytic and normochromic and non-regenerative [10, 34]. Thrombocytopenia is also reported, as well as leucocytosis and leukopenia. Occasionally, H. capsulatum may be seen within phagocytic cells on peripheral blood smears from dogs and cats [1]. On serum biochemistry, hypoalbuminemia is a common finding. Cats with liver involvement can have increased liver enzyme activity and hyperbilirubinemia. Hyperglobulinemia and azotaemia are also reported in few cats [33], as well as hypercalcaemia [45]. Abnormalities on thoracic radiographs are common and may be subclinical [1, 44]. Radiographic patterns in cats with pulmonary histoplasmosis include fine, diffuse or linear interstitial patterns, bronchointerstitial patterns, diffuse miliary or nodular interstitial patterns, alveolar patterns and/or areas of pulmonary consolidation [33]. Sternal lymphadenopathy is also reported [46]. Bone lesions on radiographs are typically osteolytic, but there may be periosteal and endosteal proliferative lesions, which are mostly found in appendicular bones with a predilection for the elbow and stifle joints [39]. A definitive diagnosis of histoplasmosis is made by cytologic or histopathologic identification of H. capsulatum in tissues (Fig. 3). The organisms are usually identified intracellularly within macrophages but can sometimes be found free in necrotic exudates and may be confused with Cryptococcus spp. [20] As for Cryptococcus infections, a variety of stains can highlight the yeasts, such as Diff-Quik and Wright stains for cytology and GMS or PAS stains for histology. The yeasts can be found on cytology of lymph nodes, lung, liver, spleen, skin or bone marrow. Serum antibody assays are available but their clinical utility has been limited by low sensitivity and specificity [47]. An antigen ELISA assay has been evaluated for the diagnosis and monitoring of histoplasmosis in cats when applied to serum and urine specimens [46, 47]. Sensitivities of 93–94% of the assay were reported in two studies when applied to urine whereas the sensitivity was only 73% when applied to serum [46, 47]. A specificity of 100% was found in one of these two studies, which included 20 cats diagnosed with other non-fungal diseases [47]. Based on the human literature, serologic cross-reactivity with other VetBooks.ir Deep Fungal Diseases 309 Fig. 3 Cytology showing intracellular Histoplasma yeast organisms fungal pathogens such as Blastomyces spp. is however expected [47]. Antigen concentrations decrease with effective anti-fungal treatment and increase in cases that were not well controlled or following relapse [46]. However, antigen elimination sometimes preceded clinical remission and four cats still had measurable antigen concentrations at the time of remission. Fungal culture and PCR can also be used to confirm a diagnosis of histoplasmosis. However, fungal culture is a hazard to laboratory workers and should therefore be performed only if necessary, and the laboratory should be warned of the possibility of a dimorphic fungal infection, so that appropriate precautions are taken. Although most cultures are positive within 2 or 3 weeks, growth may require up to 6 weeks of incubation. PCR is currently not used routinely for diagnosis but was used in a few cases to confirm the diagnoses in non-endemic areas [27, 28, 30, 48]. It can also be used when the identity of the fungus observed on histopathology is in doubt. Treatment and Prognosis Itraconazole is the treatment of choice for histoplasmosis [45]. Treatment is recommended for a minimum of 4 to 6 months and should be continued for at least 2 months after resolution of clinical signs and possibly until antigen assays are negative. The use of itraconazole may be cost-prohibitive for some clients and adverse effects are more common than with fluconazole, particularly hepatotoxicity [35]. A retrospective study comparing the outcome of 17 cats treated with fluconazole to 13 cats treated with itraconazole found no difference in mortality and relapse rate between the two groups suggesting that fluconazole may be a suitable alternative [35]. However, a lower efficacy of fluconazole compared to itraconazole, and development of fluconazole resistance during treatment has been described in people VetBooks.ir 310 J. D. Lemetayer and J. E. Sykes [49] and in a cat [50]. The fluconazole-resistant isolates also had increased MICs to voriconazole but not to itraconazole or posaconazole. Deoxycholate or lipid-complexed amphotericin B can be used initially to treat cats with severe acute pulmonary, acute disseminated, or CNS disease, after which treatment should be continued with either itraconazole or fluconazole. Other possible treatment options include posaconazole in cats that do not tolerate itraconazole or those that fail to respond to fluconazole. A short course of anti-inflammatory glucocorticoids may be useful for cats with severe pulmonary disease or CNS disease at the beginning of treatment. The prognosis depends on the extent of disease, with reported survival rates varying from 66% to 100% [35, 45]. Blastomycosis Epidemiology Blastomyces dermatitidis is also a dimorphic fungus. It is found as a mycelium in the environment and as a thick-walled budding yeast in tissues [51]. Blastomycosis is a rare disease in cats and most feline infections are identified at necropsy. A 1996 study identified 41 cases over a 30–year time frame, and blastomycosis constituted 0.005% of all feline cases in the veterinary medical database [1]. In North America, cases of blastomycosis are mostly found in the eastern and southern parts of the USA, especially the Ohio and Mississippi River Valleys, and in the Great Lakes region, as well as in Canada, especially Quebec, Ontario, Manitoba, and Saskatchewan [1, 52–54]. Blastomycosis is also endemic in Africa and India [51]. Blastomycosis was also reported in a cat from Thailand [55]. In endemic regions, B. dermatitidis is found in localized regions where soils are moist and acidic with decaying vegetation or animal excreta [52]. Inhalation of conidia produced from the mycelial phase in soil or decaying matter is the primary route of infection [51]. Direct inoculation of the organism via skin puncture wounds occurs rarely. From the lungs, the organism may disseminate via the vascular or lymphatic system, resulting in a granulomatous or pyogranulomatous inflammatory response in many organs, especially the lymph nodes, eyes, skin, bones and brain. Clinical Features in Cats A male predisposition to blastomycosis was found in one study and cats less than 4 years of age appear predisposed [1, 53, 56]. However in another case series of eight cats, most cases were female and over 7 years of age [52]. In addition, Siamese, Abyssinian, and Havana Brown cats may be predisposed [1]. Immunosuppression does not seem to play a role in predisposition to the disease [52], and cats housed strictly indoors can also be affected [52, 57, 58]. VetBooks.ir Deep Fungal Diseases 311 Fig. 4 Lateral thoracic radiograph of a cat with pulmonary blastomycosis. Courtesy University of California, Davis Veterinary Medical Teaching Hospital Diagnostic Imaging Service Duration of illness at diagnosis ranges from less than 1 week to 7 months and clinical signs include dyspnoea, cough, anorexia, lethargy, weight loss, peripheral lymphadenopathy, lameness, cellulitis of the limbs, CNS and cutaneous and ocular signs (Fig. 4) [1, 51]. Cutaneous involvement occurred in 23% of 22 affected cats [1], in 63% of eight cats in another case series [52] and in six additional cats [57, 59]. Cutaneous signs include non-ulcerated dermal masses, ulcerative skin lesions, draining abscesses or cellulitis [1, 52, 59]. Diagnostic Tests Bloodwork findings in cats with blastomycosis are non-specific and indicative of an inflammatory process, such as mild non-regenerative anaemia [52]. Hypercalcaemia and increased calcitriol concentration have also been reported [59]. A specific diagnosis of blastomycosis is usually made using cytologic examination of impression smears, lavage specimens, or aspirates (skin, lymph nodes or lungs). Cytology was diagnostic in 4/6 cases and in 4/5 cases in two studies [53, 57]. Blastomyces yeasts are round to oval, 10–20 μm in diameter, have a basophilic cytoplasm, thick and double-contoured walls and display broad-based budding [51]. A pyogranulomatous inflammatory reaction is typical, but a suppurative response predominates on occasion. Special stains such as PAS, Gridley’s fungal, and GMS can assist in the detection of the yeasts. Histology of tissue or bone biopsies, fungal culture or PCR can also be used to make a diagnosis of blastomycosis. However, culture is time- consuming and a hazard for laboratory staff. To date, PCR assays have primarily been used for research purposes [60, 61] but in one report, PCR was used to confirm a diagnosis of blastomycosis in a cat from a non-endemic country [55]. Serology has not been well evaluated in cats. In a study, only one of four cats with blastomycosis tested positive on agar gel immunodiffusion (AGID) using Blastomyces whole cell antigen [1]. 312 J. D. Lemetayer and J. E. Sykes VetBooks.ir Treatment and Prognosis Cats with blastomycosis are usually treated with itraconazole. Fluconazole appears to be less effective than itraconazole, but it may be a more appropriate treatment choice for urinary tract, prostatic and CNS infections because of improved penetration of these organs. The addition of amphotericin B for cats with severe disease such as CNS or severe disseminated disease may also be valuable [56, 62]. However, two cats with severe disease treated with amphotericin B did not respond well to treatment [63]. Newer triazoles, including voriconazole, posaconazole and isavuconazole, have activity against B. dermatitidis. Voriconazole and posaconazole have both been successfully used to treat severe blastomycosis in humans, especially cases with CNS involvement [64], but in general voriconazole should be avoided in cats due to their susceptibility to voriconazole toxicity. Clinical signs and radiographic lesions can worsen in the first few days of treatment as a result of the inflammatory response to dying organisms. A short course of glucocorticoids at an anti-inflammatory dose should be considered for patients with CNS involvement and severe respiratory disease, although whether this ultimately improves outcome is not known. In one study, 4 of 8 cats responded favourably to either itraconazole or fluconazole [52] and 4 of 7 responded favourably to surgical resection of cutaneous lesions and administration of ketoconazole and potassium iodide in another study [1]. However only 1 of 4 cats survived with itraconazole treatment in another study [57]. Coccidioidomycosis Epidemiology Coccidioidomycosis is also a rare disease worldwide in cats. The largest case series (48 cats) was reported from Arizona, including 41 cases that were diagnosed over 3 years [65]. Coccidioidomycosis is endemic to the semiarid desert regions of the southwestern USA, southern and central California, southern Arizona, southern New Mexico, western Texas, southern Nevada and Utah, as well as northern Mexico, and parts of Central and South America [66]. Coccidioidomycosis is caused by Coccidioides immitis and Coccidioides posadasii. Coccidioides immitis is mostly found in California and C. posadasii is found elsewhere [67]. No significant differences in morphology or disease course have been noted between the two organisms [68]. However, coccidioidomycosis is extremely rare in California, suggesting that cats may be less susceptible to C. immitis infections, or that feline exposure occurs to a greater degree in areas where C. posadasii resides [67]. Coccidioides spp. is present in soil as a mycelium which germinate to form arthroconidia that are released and dispersed when the soil is disturbed. Infection occurs following inhalation of these arthrospores but also rarely by direct inoculation of organisms into skin. Dissemination occurs when the immune system is incapable of containing replication of the organism to the lungs. Deep Fungal Diseases 313 VetBooks.ir Clinical Features in Cats The mean age of affected cats at diagnosis was 6.2 years in one study [1] and 9 years in another, [68] with age ranging from 3 to 17 years. Female cats were overrepresented in one study with 12 of 17 cases being female [68]. There is no breed predilection reported and immunosuppression does not seem to play a role in the development of the disease [68]. Although having access to outdoors is likely a risk factor, cats housed exclusively indoors can also develop coccidioidomycosis [68, 69]. The reported duration of clinical signs before diagnosis of coccidioidomycosis in cats ranged from less than 1 week to 1 year, with up to 86% of the animals having clinical signs for less than a month before diagnosis [1, 65, 68]. Cats are mostly diagnosed when the disease has disseminated, and dermatologic signs are the most common presenting complaints in cats with disseminated disease. Dermatological signs were seen in 56% of 48 cats [65]. Cutaneous lesions include plaque-like nodules, nodules with draining tracts, alopecia, scarring and induration with draining tracts, papules, pustules and lingual ulcerations [65, 68, 70]. Regional lymphadenopathy may also be present. More than half of the population of cats with dermatologic signs also had clinical signs of systemic illness such as fever, lethargy, weight loss, anorexia, lameness, or cough [68]. Respiratory signs such as cough or tachypnoea were noted in only 25% of cats with coccidioidomycosis [65]. However, lung involvement is probably more common since thoracic radiographs were not performed on many cats of this study and lung infection was found in nearly all cases at necropsy in another study [66]. Hilar lymphadenopathy, interstitial or mixed interstitial and bronchointerstitial pulmonary patterns and rarely pleural thickening or effusion are found on thoracic radiographs [65]. Other reported clinical signs include ocular signs such as chorioretinitis, anterior uveitis, retinal detachment, panophthalmitis; CNS signs (with intracranial or spinal cord lesions) such as seizures, hyperesthesia, behavioural changes, pelvic limb weakness and ataxia; and musculoskeletal signs such as lameness [65, 66, 69, 71, 72]. Restrictive pericarditis, pericardial effusion and right sided heart failure are reported in dogs with coccidioidomycosis but have not been described in cats [66]. However, pericardial involvement was found at necropsy in 26% of cats with coccidioidomycosis despite a lack of clinical signs referable to heart disease in all cats of the study [66]. Diagnostic Tests In cats with coccidioidomycosis, laboratory abnormalities include nonregenerative anaemia, leucocytosis, leukopenia, hypoalbuminemia and hyperglobulinemia [65, 72]. In contrast to humans, eosinophilia has not been reported in cats with coccidioidomycosis [73]. The sensitivity and specificity of serology for the diagnosis of coccidioidomycosis in cats is unknown. Most commercial laboratories perform AGID assays for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. In 39 VetBooks.ir 314 J. D. Lemetayer and J. E. Sykes cats with coccidioidomycosis, all cats were seropositive at some point during their illness [65]. At the time of diagnosis, 29 cats were positive for IgM (tube precipitin) antibodies and six cats were negative for IgM but positive for IgG (complement fixating) antibodies. IgG antibody titres ranged from 1:2 to 1:128, with 31 cats having titres ≥1:16. Cytologic confirmation may be made by evaluation of aspirates of affected lymph nodes, skin lesions, lungs, pleural effusion, as well as bronchoalveolar lavage but is relatively insensitive for the diagnosis of coccidioidomycosis when compared with other deep mycoses [67]. On cytology, a granulomatous or pyogranulomatous inflammation is often seen, with sometimes rare multinucleated giant cells, few eosinophils, and/or reactive lymphocytes. Occasionally a suppurative inflammatory response predominates. If seen, the organism appears as a large (10–80 μm) round, deeply basophilic, double-walled spherule that may contain endospores. The endospores are 2–5 μm in diameter, are surrounded by a thin, non-staining halo, and have small, round to oval, densely aggregated, eccentric nuclei. Diff-Quik and Wright stains can be used to facilitate visualization. Similarly, multiple biopsy samples may need to be evaluated to identify the organism histologically. The use of special stains such as PAS or GMS stains may be required. Coccidioides spp. structures were seen on cytology or histology of exudates or tissue specimens in only 56% of 48 cats [65]. Cultures of exudates or tissues grew Coccidioides in only 23% of these cats and therefore a negative culture does not rule out a diagnosis of coccidioidomycosis. Coccidioides spp. can be isolated on routine fungal media, but growth in culture represents a serious health hazard to laboratory personnel and should only be performed if necessary and by suitably equipped laboratories. The use of PCR assays to aid in the diagnosis of coccidioidomycosis has not been reported in cats. Treatment and Prognosis Itraconazole or fluconazole are typically used for the treatment of feline coccidioidomycosis, but ketoconazole has been used historically. Of 53 cats diagnosed with coccidioidomycosis and treated mostly with ketoconazole, 67% survived with treatment [1]. The average treatment duration was 10 months. Fluconazole may be used for patients with ocular and CNS involvement, because of its superior penetration of the eyes and CNS [71, 72]. Itraconazole is preferred for animals with bone involvement and is recommended for animals that fail to respond to treatment with fluconazole. In people, a trend toward slightly greater efficacy of itraconazole over fluconazole was found in non-meningeal cases but it was not statistically significant [74]. In addition, the use of amphotericin B is recommended for the treatment of human patients with very severe and/or rapidly progressing VetBooks.ir Deep Fungal Diseases 315 acute pulmonary or disseminated coccidioidomycosis, followed by fluconazole once patients have stabilized [75]. In human patients who fail standard therapy, treatment with posaconazole or voriconazole has been reported with approximately 70% of improvement and slightly better outcomes with posaconazole compared to voriconazole [72, 76]. The use of echinocandins in combination with voriconazole in refractory patients was also reported with success [77]. However, voriconazole should be avoided in cats due to their susceptibility to severe voriconazole toxicity. Box 2: Mould Infections • Mould infections are less prevalent in cats than in dogs. • Cutaneous signs are rare with aspergillosis in cats. Aspergillus spp. cause sino-nasal aspergillosis and sino-orbital aspergillosis in cats with a predisposition for brachycephalic cats. They also rarely cause disseminated disease, which is usually seen in immunodeficient cats. • Hyalohyphomycosis and phaeohyphomycosis are cutaneous and subcutaneous infections usually acquired from traumatic implantation of fungi from the environment. Most cats are immunocompetent. • Zygomycosis is acquired by inhalation, ingestion or contamination of wounds. Concurrent immunosuppressive conditions are common. • Pythiosis is caused by the penetration of acquired motile biflagellate zoospores in aquatic environments through damaged skin or GI mucosa. It is mostly manifested as cutaneous and subcutaneous lesions in cats. • Complete surgical excision of the affected tissue with wide margins is the treatment of choice for hyalohyphomycosis, phaeohyphomycosis, zygomycosis and pythiosis as treatment with anti-fungal drugs is usually not curative. Aspergillosis Epidemiology Aspergillus species are ubiquitous saprophytic moulds that are found worldwide in soil and decaying vegetation [78]. Species affecting cats are usually included in the A. fumigatus complex (Aspergillus fumigatus, Neosartorya spp., Aspergillus lentulus and Aspergillus udagawae) [79]. Members of the A. fumigatus complex cannot be identified reliably by phenotypic testing alone and require molecular techniques for identification [79]. Aspergillus flavus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus udagawae and Aspergillus felis have also been detected in a few cases [78, 80, 81]. 316 J. D. Lemetayer and J. E. Sykes VetBooks.ir Clinical Features in Cats The most common forms of aspergillosis in cats are sino-nasal aspergillosis (SNA) and sino-orbital aspergillosis (SOA). The development of localized sino-nasal or sino-orbital infection suggest defects of local defence mechanisms. In normal conditions, infections are prevented by physical barriers such as mucociliary clearance, and the local innate immune system (macrophages and neutrophils) [82]. Brachycephalic breeds, especially Persian or Himalayan cats, are predisposed [78]. It has been suggested that this may result from reduced mucociliary clearance [78]. Other possible risk factors include previous viral upper respiratory tract infections, inflammatory rhinitis and use of glucocorticoids or less likely previous antibiotic treatment [80, 82]. No association between aspergillosis and feline retrovirus infections has been reported [79]. Affected cats range in age from 1.5 to 13 years (median, 5 years) with no clear sex predisposition [79]. The duration of clinical signs before diagnosis ranged from less than 5 days to more than 6 weeks in one study [ 1]. Clinical signs of SNA include sneezing, uni- or bilateral serous to mucopurulent nasal discharge, and sometimes epistaxis and less commonly stertorous breathing, granuloma formation, soft tissue masses protruding from the nares, and bone lysis. SOA is a more invasive form of SNA, with involvement of the retrobulbar space. Clinical signs include unilateral exophthalmos, third eyelid prolapse, conjunctival hyperaemia and keratitis. With severe retrobulbar involvement, a mass may be observed in the caudal aspect of the oral cavity (Fig. 5). CNS involvement, regional lymphadenopathy and fever have also been described. Systemic aspergillosis in cats is rare and is usually associated with immune- deficiency. Aspergillus niger pneumonia was reported in two cats with diabetes mellitus [83], and disseminated aspergillosis in 38 cats with more than half of these cats Fig. 5 Mass in the caudal aspect of the oral cavity of a cat with sino-orbital aspergillosis VetBooks.ir Deep Fungal Diseases 317 having a concurrent immune-suppressive condition (mainly panleukopenia, FeLV and feline infectious peritonitis) [1, 84]. Cutaneous disease is also a very uncommon manifestation of aspergillosis in cats. Cutaneous involvement of the naso-ocular region of a cat with naso-sinusal aspergillosis was reported [85] and Aspergillus vitricola was cultured from an auricular lesion in another cat [86]. Diagnostic Tests The diagnosis of SNA and SOA requires a combination of tests such as imaging studies, rhinoscopy, cytology and/or histology, and fungal cultures. Imaging modalities such as computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the head can be used to evaluate for destruction of the nasal turbinates, nasal septum, cribriform plate, and involvement of the sinus and retrobulbar space. On rhinoscopy, destruction of the nasal turbinates and white-grey plaques may be seen [87]. Cytologic examination of blind or rhinoscopy-directed mucosal swabs, brush specimens of the nasal cavity, nasal biopsies from cats with SNA, or cytologic examination of ultrasound- or CT-guided aspirates of retrobulbar masses from cats with SOA often reveal mixed, predominantly pyogranulomatous inflammation. Sometimes, Aspergillus hyphae are seen but false-negative results are common. Aspergillus fumigatus can usually grow in few days to few weeks on routine laboratory media and does not represent a significant hazard to laboratory personnel. In the absence of supportive rhinoscopic, cytologic or histopathologic findings, positive cultures from the nasal cavity require cautious interpretation because Aspergillus spp. are ubiquitous and therefore false positive results are not uncommon. Whenever possible, fungal culture should be submitted from samples collected by rhinoscopic guidance in order to increase sensitivity [88]. Growth of Aspergillus from aspirates or biopsy specimens from a normally sterile site such as a retrobulbar mass strongly suggests a diagnosis of SOA. In one study, fungal cultures were positive in 22/23 cats with SNA or SOA [79] but in another study the sensitivity of culture was lower. [89] The use of serologic tests (antibody and antigen tests) for diagnosis of aspergillosis in cats has been unreliable [78, 79, 81, 87, 89]. Treatment and Prognosis Treatment of SNA in cats has been similar to treatment used in dogs. Intranasal infusion of clotrimazole for 1 hour was described in three cats with good outcomes [82, 87]. Treatment of SOA and disseminated aspergillosis requires systemic antifungal treatment (monotherapy or a combination of two anti-fungal treatments) but prognosis is guarded to poor. Anti-fungal drugs reported in the treatment of SOA and disseminated aspergillosis include itraconazole, amphotericin B, posaconazole, voriconazole, terbinafine, caspofungin and micafungin [79, 90–92]. Voriconazole is VetBooks.ir 318 J. D. Lemetayer and J. E. Sykes not recommended because of the potential for severe toxicity in cats. Fluconazole and flucytosine are not recommended because Aspergillus species are intrinsically resistant to these anti-fungal drugs [93]. In addition, high minimum inhibitory concentrations (MIC) for ketoconazole are common among Aspergillus species. In a 2015 Australian study evaluating anti-fungal resistance in canine and feline isolates of Aspergillus fumigatus, the vast majority of isolates had low MICs for itraconazole, voriconazole, posaconazole, clotrimazole and enilconazole [93]. Interestingly, seven isolates had high MICs for amphotericin B. Aspergillus felis exhibits high MICs to many anti-fungal drugs [94]. High MICs of A. felis isolates to at least one of the triazoles, and cross resistance among several triazoles were observed. In addition, a high MIC for caspofungin was described for one isolate. Other Moulds Hyalohyphomycosis Hyalohyphomycosis is caused by non-dematiaceous (hyaline, nonpigmented) moulds. A retrospective study from the UK evaluating 77 cats with nodular granulomatous skin lesions caused by fungi found that the most frequent pathogens were hyalohyphomycetes [95]. Reported species associated with disease in cats include Fusarium, Acremonium, Paecilomyces spp. and Metarhizium spp., among others [95–101]. These are filamentous fungi found in soil and on plants and have a worldwide distribution. Hyalohyphomycosis has been diagnosed in cats with cutaneous nodules, rhinosinusitis, pneumonia, pododermatitis and keratitis. Diagnosis is made by cytology, histology and fungal culture. Cytological and histological examination usually reveals pyogranulomatous inflammation in association with nonpigmented, frequently septate, branching hyphae that are often pleomorphic. Culture and proper identification of the pathogen is recommended to guide in the choice of anti-fungal treatment because some species are predictably less susceptible to conventional anti-fungal drugs. However, because these fungi are common laboratory contaminants and can sometimes be isolated from the skin or hair of healthy animals, positive cultures from non-sterile sites should be considered in light of the clinical picture. Complete surgical excision of the affected tissue with wide margins is the treatment of choice whenever possible, followed by anti-fungal therapy for 3–6 months. Drugs used most often to treat hyalohyphomycosis in small animals include itraconazole and amphotericin B, but different fungal species vary in their susceptibility to anti-fungal drugs. Posaconazole and the echinocandins, such as caspofungin, may be more active against these fungi than itraconazole. Fusarium spp. are intrinsically resistant to glucan synthesis inhibitors such as caspofungin; however, in combination with amphotericin B, they can have a synergistic action [98]. Deep Fungal Diseases 319 VetBooks.ir Phaeohyphomycosis Phaeohyphomycetes are dematiaceous filamentous fungi that contain a melanin- like pigment in the walls of the hyphae and occasionally cause opportunistic infections in cats. The pigment plays important role in virulence and pathogenicity of these pathogens as it aids fungal evasion of the host immune response by preventing hydrolytic enzymatic attack and scavenging of free radicals liberated by phagocytic cells during then oxidative burst [102]. Species that have caused disease in cats include Exophiala spp., Alternaria spp., Cladosporium spp., Phialophora spp., Cladophialophora spp., Ulocladium spp., Microsphaeropsis spp., Fonsecae spp., Moniliella spp. and Aureobasidium spp., among others [86, 98, 102–115]. Cladosporium spp. may be more likely to disseminate in immunocompetent cats. In addition, among the genus Cladophialophora, Cladophialophora bantiana shows a marked neurotropism in comparison with other fungi. [109, 115, 116] Phaeohyphomycetes are found in soil, wood and decomposing plant debris worldwide. Infections usually result from cutaneous inoculation resulting in cutaneous and subcutaneous infections (Fig. 6). Most lesions in cats occur on the head or extremities and usually a single nodule is present. Systemic signs of illness are usually absent. Rarely, ingestion or inhalation of spores might also occur and cause deep infection [109]. Factors predisposing cats to phaeohyphomycoses may include treatment with immunosuppressive agents; concurrent disease; or age-related, non-specific loss of immunity. However, no obvious immunosuppression is found in most cases [103] although the majority of cats in reports were not tested for FIV and FeLV. Diagnosis is made by cytology, histology and fungal culture. Cytology of exudates usually reveals pyogranulomatous inflammation that may contain pigmented fungal hyphae, pseudohyphae, and/or yeast-like cells. Fungal culture is recommended for proper diagnosis. An indirect ELISA has been developed for the Fig. 6 Subcutaneous phaeohyphomycosis associated with swelling of the distal limb of a cat VetBooks.ir 320 J. D. Lemetayer and J. E. Sykes detection of anti-Alternaria IgG antibodies in serum in domestic cats. However, cats with disease caused by Alternaria did not have significantly higher concentrations of antibody than healthy cats or cats with other diseases [117]. Complete surgical excision of the affected tissue with wide margins is the treatment of choice whenever possible, followed by anti-fungal therapy for 3 to 6 months. If complete surgical removal is not possible, the prognosis is guarded. Indeed, phaeohyphomycoses often have recrudescent clinical courses and are refractory to many anti-fungal drugs. In cases of disseminated or cerebral infection, treatment is rarely successful, and prognosis is poor. Ketoconazole, itraconazole, amphotericin B, flucytosine and terbinafine have been used with variable results to treat phaeohyphomycosis in cats [111, 113]. Combination therapy with terbinafine and an azole anti-fungal drug such as itraconazole or posaconazole has been suggested [114]. If improvement is seen, long-term treatment (6 to 12 months) is recommended to prevent recurrence of the lesions. Zygomycosis Zygomycetes are opportunistic organisms present in the soil, water, decaying matter and faeces. They include organisms that belong to the genera Basidiobolus and Conidiobolus in the order Entomophthorales, and the genera Rhizopus, Absidia, Mucor, Saksenaea, and others in the order Mucorales [118]. Infection is believed to be acquired by inhalation, ingestion or contamination of wounds. Rare reports exist of Mucor spp. infections in cats, including a case of cerebral mycosis, subcutaneous infection and duodenal perforation caused by Rhizomucor spp. [119–121] In addition, 12 cases of suspected mucormycosis diagnosed using histology were reported in a necropsy study [84]. Lesions in most of these cats involved the GI tract or lungs and 6 of the 12 cats had possible immune-suppressive conditions. Conidiobolus infection was suspected in a 3-year-old cat with an ulcerative lesion of the hard palate [118]. A definitive diagnosis of zygomycosis is made based on cytological or histopathological examination in combination with fungal culture. Cytological and histological findings include pyogranulomatous, suppurative or eosinophilic inflammation. Broad (>8 μm), poorly septate hyphae with thick prominent eosinophilic sleeves are sometimes observed. Microscopic examination of macerated tissue that has been digested in 10% potassium hydroxide may be more likely to reveal the hyphal elements. Staining of histopathological specimens with GMS and PAS stains can also assist in visualization of hyphal elements. Wide surgical excision (whenever possible) combined with long-term medical treatment is recommended for zygomycosis. Zygomycetes are variably susceptible to anti-fungal drugs. Posaconazole and amphotericin B are considered the most effective anti-fungal drugs for Mucor infections in humans [120]. Some cases of human zygomycosis also had good outcome with itraconazole treatment [122, 123]. Deep Fungal Diseases 321 VetBooks.ir Pythiosis Pythiosis is caused by the aquatic oomycete Pythium insidiosum. Oomycetes are soil and aquatic organisms that are phylogenetically distant from the fungi, and more closely related to algae [118]. Chitin, an essential component of the fungal cell wall, is generally lacking in the oomycete cell wall, which instead contains predominately cellulose and β–glucan [118]. Ergosterol is also not a principal sterol in the oomycete cell membrane contrary to fungal organisms. The infective form of P. insidiosum is a motile biflagellate zoospore, which is released into aquatic environments and causes infection by penetrating damaged skin or GI mucosa. Pythiosis is most commonly encountered in tropical and subtropical climates; however, infections in animals from temperate areas have also been reported [124]. It is endemic in the USA (primarily in the Gulf coast states), and cases also occur in Southeast Asia, eastern coastal Australia, New Zealand, and South America [118]. Pythiosis is extremely rare in cats and usually manifests as subcutaneous lesions (including in the inguinal, tail head, or periorbital regions), draining nodular lesions or ulcerated plaque-like lesions localized on the extremities [118]. One cat with nasal and retrobulbar mass [125], one cat with a sublingual mass [126] and two cats with gastro-intestinal pythiosis [124] were also reported. Specific breed and sex predilections have not been observed but young cats may be predisposed. In 10 cats with cutaneous lesions caused by P. insidiosum, five were younger than 10 months old, with an age range of 4 months to 9 years [118]. Cytological and histological examinations show eosinophilic and granulomatous inflammation with prominent fibrosis and necrosis [124]. To complicate the diagnosis, P. insidiosum typically does not stain with H&E stain and may be present in low numbers. The hyphae appear within necrotic areas and granulomas as clear round or oval to elongate structures delineated by a narrow rim of eosinophilic material. It also stains poorly with PAS but can be observed with GMS stain. The hyphae are infrequently septate, branching and measure from 2.5 to 8.9 mm in diameter with thick walls in comparison to the septa and with almost parallel sides [124]. Differentiation between pythiosis, lagenidiosis, and zygomycosis based on routine histologic examination is not usually possible because differences in their histologic characteristics are subtle, although Mucor spp. stain equally well using H&E, PAS, and GMS stains. Culture of tissues or the use of immunohistochemistry, PCR and/or serology can aid in diagnosis [124]. Culture of exudates is usually unsuccessful and culture of tissues requires specific specimen handling (unrefrigerated tissues that are kept moist) and culture techniques. The identity of organisms isolated in culture can be confirmed using PCR sequencing [127]. In addition, immunoblot serology and ELISA techniques have been used successfully to support the diagnosis of pythiosis in a few cats [124, 125, 128]. The treatment of choice for pythiosis is aggressive surgical resection of infected tissues with 3–4-cm margins whenever possible. When used alone, medical therapy VetBooks.ir 322 J. D. Lemetayer and J. E. Sykes for pythiosis is typically unrewarding. This is likely because ergosterol, which is the target for most anti-fungal drugs, is generally lacking in the oomycete cell membrane. In dogs, a combination of itraconazole and terbinafine may be effective for resolution of incompletely resected or nonresectable lesions. Ketoconazole has also been used [125]. The short-term use of prednisone is also recommended in dogs with gastrointestinal pythiosis to improve clinical signs (vomiting, decreased appetite) [127]. References 1. Davies C, Troy GC. Deep mycotic infections in cats. J Am Anim Hosp Assoc. 1996;32:380–91. 2. Sykes JE, Taboada J. Histoplasmosis. In: Sykes JE, editor. Canine and feline infectious diseases. St Louis: Elsevier Saunders; 2014. p. 587–98. 3. Kano R, Hosaka S, Hasegawa A. First isolation of Cryptococcus magnus from a cat. Mycopathologia. 2004;157:263–4. 4. Poth T, Seibold M, Werckenthin C, Hermanns W. First report of a Cryptococcus magnus infection in a cat. Med Mycol. 2010;48:1000–4. 5. Kano R, Kitagawat M, Oota S, Oosumi T, Murakami Y, Tokuriki M, et al. First case of feline systemic Cryptococcus albidus infection. Med Mycol. 2008;46:75–7. 6. O’Brien CR, Krockenberger MB, Wigney DI, Martin P, Malik R. Retrospective study of feline and canine cryptococcosis in Australia from 1981 to 2001: 195 cases. Med Mycol. 2004;42:449–60. 7. Lester SJ, Malik R, Bartlett KH, Duncan CG. Cryptococcosis: update and emergence of Cryptococcus gattii. Vet Clin Pathol. 2011;40:4–17. 8. Pennisi MG, Hartmann K, Lloret A, Ferrer L, Addie D, Belak S, et al. Cryptococcosis in cats: ABCD guidelines on prevention and management. J Feline Med Surg. 2013;15:611–8. 9. McGill S, Malik R, Saul N, Beetson S, Secombe C, Robertson I, et al. Cryptococcosis in domestic animals in Western Australia: a retrospective study from 1995–2006. Med Mycol. 2009;47:625–39. 10. Malik R, Wigney DI, Muir DB, Gregory DJ, Love DN. Cryptococcosis in cats: clinical and mycological assessment of 29 cases and evaluation of treatment using orally administered fluconazole. J Med Vet Mycol. 1992;30:133–44. 11. Trivedi SR, Sykes JE, Cannon MS, Wisner ER, Meyer W, Sturges BK, et al. Clinical features and epidemiology of cryptococcosis in cats and dogs in California: 93 cases (1988–2010). J Am Vet Med Assoc. 2011;239:357–69. 12. Jacobs GJ, Medleau L, Calvert C, Brown J. Cryptococcal infection in cats: factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats. J Vet Intern Med. 1997;11:1–4. 13. Castrodale LJ, Gerlach RF, Preziosi DE, Frederickson P, Lockhart SR. Prolonged incubation period for Cryptococcus gattii infection in cat, Alaska, USA. Emerg Infect Dis. 2013;19:1034–5. 14. Myers A, Meason-Smith C, Mansell J, Krockenberger M, Peters-Kennedy J, Ross Payne H, et al. Atypical cutaneous cryptococcosis in four cats in the USA. Vet Dermatol. 2017;28:405–e97. 15. Odom T, Anderson JG. Proliferative gingival lesion in a cat with disseminated cryptococcosis. J Vet Dent. 2000;17:177–81. 16. Siak MK, Paul A, Drees R, Arthur I, Burrows AK, Tebb AJ, et al. Otogenic meningoencephalomyelitis due to Cryptococcus gattii (VGII) infection in a cat from Western Australia. JFMS Open Rep. 2015;1:2055116915585022. 17. Sykes JE, Malik R. Cryptococcosis. In: Sykes JE, editor. Canine and feline infectious diseases. St Louis: Elsevier Saunders; 2014. p. 599–612. VetBooks.ir Deep Fungal Diseases 323 18. Trivedi SR, Malik R, Meyer W, Sykes JE. Feline cryptococcosis: impact of current research on clinical management. J Feline Med Surg. 2011;13:163–72. 19. Guess T, Lai H, Smith SE, Sircy L, Cunningham K, Nelson DE, et al. Size matters: measurement of capsule diameter in Cryptococcus neoformans. J Vis Exp. 2018;132:1–10. 20. Ranjan R, Jain D, Singh L, Iyer VK, Sharma MC, Mathur SR. Differentiation of histoplasma and cryptococcus in cytology smears: a diagnostic dilemma in severely necrotic cases. Cytopathology. 2015;26:244–9. 21. Sykes JE, Hodge G, Singapuri A, Yang ML, Gelli A, Thompson GR 3rd. In vivo development of fluconazole resistance in serial Cryptococcus gattii isolates from a cat. Med Mycol. 2017;55:396–401. 22. Kano R, Okubo M, Yanai T, Hasegawa A, Kamata H. First isolation of azole-resistant Cryptococcus neoformans from feline cryptococcosis. Mycopathologia. 2015;180:427–33. 23. Mondon P, Petter R, Amalfitano G, Luzzati R, Concia E, Polacheck I, et al. 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Fischer NM, Favrot C, Monod M, Grest P, Rech K, Wilhelm S. A case in Europe of feline histoplasmosis apparently limited to the skin. Vet Dermatol. 2013;24:635–8. 29. Percy DH. Feline histoplasmosis with ocular involvement. Vet Pathol. 1981;18:163–9. 30. Larsuprom L, Duangkaew L, Kasorndorkbua C, Chen C, Chindamporn A, Worasilchai N. Feline cutaneous histoplasmosis: the first case report from Thailand. Med Mycol Case Rep. 2017;18:28–30. 31. Mavropoulou A, Grandi G, Calvi L, Passeri B, Volta A, Kramer LH, et al. Disseminated histoplasmosis in a cat in Europe. J Small Anim Pract. 2010;51:176–80. 32. Kasuga T, White TJ, Koenig G, McEwen J, Restrepo A, Castaneda E, et al. Phylogeography of the fungal pathogen Histoplasma capsulatum. Mol Ecol. 2003;12:3383–401. 33. Bromel C, Sykes JE. Histoplasmosis in dogs and cats. Clin Tech Small Anim Pract. 2005;20:227–32. 34. Aulakh HK, Aulakh KS, Troy GC. Feline histoplasmosis: a retrospective study of 22 cases (1986–2009). J Am Anim Hosp Assoc. 2012;48:182–7. 35. Reinhart JM, KuKanich KS, Jackson T, Harkin KR. Feline histoplasmosis: fluconazole therapy and identification of potential sources of Histoplasma species exposure. J Feline Med Surg. 2012;14:841–8. 36. Atiee G, Kvitko-White H, Spaulding K, Johnson M. Ultrasonographic appearance of histoplasmosis identified in the spleen in 15 cats. Vet Radiol Ultrasoun. 2014;55:310–4. 37. Gingerich K, Guptill L. Canine and feline histoplasmosis: a review of a widespread fungus. Vet Med. 2008;103:248–64. 38. Clinkenbeard KD, Cowell RL, Tyler RD. Disseminated histoplasmosis in cats: 12 cases (1981–1986). J Am Vet Med Assoc. 1987;190:1445–8. 39. Wolf AM. Histoplasma capsulatum osteomyelitis in the cat. J Vet Intern Med. 1987;1:158–62. 40. Carneiro RA, Lavalle GE, Araujo RB. Cutaneous histoplasmosis in cat: a case report. Arq Bras Med Vet Zoo. 2005;57:158–61. 41. Tamulevicus AM, Harkin K, Janardhan K, Debey BM. Disseminated histoplasmosis accompanied by cutaneous fragility in a cat. J Am Anim Hosp Assoc. 2011;47:E36–41. VetBooks.ir 324 J. D. Lemetayer and J. E. Sykes 42. Vinayak A, Kerwin SC, Pool RR. Treatment of thoracolumbar spinal cord compression associated with Histoplasma capsulatum infection in a cat. J Am Vet Med Assoc. 2007;230:1018–23. 43. Lamm CG, Rizzi TE, Campbell GA, Brunker JD. Pathology in practice. Histoplasma capsulatum Infections. J Am Vet Med Assoc. 2009;235:155–7. 44. Taylor AR, Barr JW, Hokamp JA, Johnson MC, Young BD. Cytologic diagnosis of disseminated histoplasmosis in the wall of the urinary bladder of a cat. J Am Anim Hosp Assoc. 2012;48:203–8. 45. Hodges RD, Legendre AM, Adams LG, Willard MD, Pitts RP, Monce K, et al. Itraconazole for the treatment of histoplasmosis in cats. J Vet Intern Med. 1994;8:409–13. 46. Hanzlicek AS, Meinkoth JH, Renschler JS, Goad C, Wheat LJ. Antigen concentrations as an indicator of clinical remission and disease relapse in cats with histoplasmosis. J Vet Intern Med. 2016;30:1065–73. 47. Cook AK, Cunningham LY, Cowell AK, Wheat LJ. Clinical evaluation of urine Histoplasma capsulatum antigen measurement in cats with suspected disseminated histoplasmosis. J Feline Med Surg. 2012;14:512–5. 48. Klang A, Loncaric I, Spergser J, Eigelsreiter S, Weissenbock H. Disseminated histoplasmosis in a domestic cat imported from the USA to Austria. Med Mycol Case Rep. 2013;2:108–12. 49. Spec A, Connoly P, Montejano R, Wheat LJ. In vitro activity of isavuconazole against fluconazole-resistant isolates of Histoplasma capsulatum. Med Mycol. 2018;56:834–7. 50. Renschler JS, Norsworthy GD, Rakian RA, Rakian AI, Wheat LJ, Hanzlicek AS. Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep. 2017;3:2055116917743364. 51. Bromel C, Sykes JE. Epidemiology, diagnosis, and treatment of blastomycosis in dogs and cats. Clin Tech Small Anim Pract. 2005;20:233–9. 52. Gilor C, Graves TK, Barger AM, O’Dell-Anderson K. Clinical aspects of natural infection with Blastomyces dermatitidis in cats: 8 cases (1991–2005). J Am Vet Med Assoc. 2006;229:96–9. 53. Davies JL, Epp T, Burgess HJ. Prevalence and geographic distribution of canine and feline blastomycosis in the Canadian prairies. Can Vet J. 2013;54:753–60. 54. Easton KL. Cutaneous North American blastomycosis in a Siamese cat. Can Vet J. 1961;2:350–1. 55. Duangkaew L, Larsuprom L, Kasondorkbua C, Chen C, Chindamporn A. Cutaneous blastomycosis and dermatophytic pseudomycetoma in a Persian cat from Bangkok, Thailand. Med Mycol Case Rep. 2017;15:12–5. 56. Miller PE, Miller LM, Schoster JV. Feline blastomycosis – a report of 3 cases and literature- review (1961 to 1988). J Am Anim Hosp Assoc. 1990;26:417–24. 57. Blondin N, Baumgardner DJ, Moore GE, Glickman LT. Blastomycosis in indoor cats: suburban Chicago, Illinois, USA. Mycopathologia. 2007;163:59–66. 58. Houseright RA, Webb JL, Claus KN. Pathology in practice. Blastomycosis in an indoor-only cat. J Am Vet Med Assoc. 2015;247:357–9. 59. Stern JA, Chew DJ, Schissler JR, Green EM. Cutaneous and systemic blastomycosis, hypercalcemia, and excess synthesis of calcitriol in a domestic shorthair cat. J Am Anim Hosp Assoc. 2011;47:e116–20. 60. Meece JK, Anderson JL, Klein BS, Sullivan TD, Foley SL, Baumgardner DJ, et al. Genetic diversity in Blastomyces dermatitidis: implications for PCR detection in clinical and environmental samples. Med Mycol. 2010;48:285–90. 61. Sidamonidze K, Peck MK, Perez M, Baumgardner D, Smith G, Chaturvedi V, et al. Real- time PCR assay for identification of Blastomyces dermatitidis in culture and in tissue. J Clin Microbiol. 2012;50:1783–6. 62. Smith JR, Legendre AM, Thomas WB, LeBlanc CJ, Lamkin C, Avenell JS, et al. Cerebral Blastomyces dermatitidis infection in a cat. J Am Vet Med Assoc. 2007;231:1210–4. 63. Breider MA, Walker TL, Legendre AM, VanEe RT. Blastomycosis in cats: five cases (1979– 1986). J Am Vet Med Assoc. 1988;193:570–2. 64. McBride JA, Gauthier GM, Klein BS. Clinical manifestations and treatment of blastomycosis. Clin Chest Med. 2017;38:435–49. VetBooks.ir Deep Fungal Diseases 325 65. Greene RT, Troy GC. Coccidioidomycosis in 48 cats – a retrospective study (1984–1993). J Vet Intern Med. 1995;9:86–91. 66. Graupmann-Kuzma A, Valentine BA, Shubitz LF, Dial SM, Watrous B, Tornquist SJ. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc. 2008;44:226–35. 67. Sykes JE. Coccidioidomycosis. In: Sykes JE, editor. Canine and feline infectious diseases. St Louis: Elsevier Saunders; 2014. p. 613–23. 68. Simoes DM, Dial SM, Coyner KS, Schick AE, Lewis TP. Retrospective analysis of cutaneous lesions in 23 canine and 17 feline cases of coccidiodomycosis seen in Arizona, USA (2009–2015). Vet Dermatol. 2016;27:346. 69. Foureman P, Longshore R, Plummer SB. Spinal cord granuloma due to Coccidioides immitis in a cat. J Vet Intern Med. 2005;19:373–6. 70. Amorim I, Colimao MJ, Cortez PP, Dias Pereira P. Coccidioidomycosis in a cat imported from the USA to Portugal. Vet Rec. 2011;169: 232a. 71. Bentley RT, Heng HG, Thompson C, Lee CS, Kroll RA, Roy ME, et al. Magnetic resonance imaging features and outcome for solitary central nervous system Coccidioides granulomas in 11 dogs and cats. Vet Radiol Ultrasoun. 2015;56:520–30. 72. Tofflemire K, Betbeze C. Three cases of feline ocular coccidioidomycosis: presentation, clinical features, diagnosis, and treatment. Vet Ophthalmol. 2010;13:166–72. 73. Alzoubaidi MSS, Knox KS, Wolk DM, Nesbit LA, Jahan K, Luraschi-Monjagatta C. Eosinophilia in coccidioidomycosis. Am J Resp Crit Care. 2013;187 74. Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133:676–86. 75. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Geertsma F, Hoover SE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the treatment of coccidioidomycosis. Clin Infect Dis. 2016;63:E112–E46. 76. Kim MM, Vikram HR, Kusne S, Seville MT, Blair JE. Treatment of refractory coccidioidomycosis with voriconazole or posaconazole. Clin Infect Dis. 2011;53:1060–6. 77. Levy ER, McCarty JM, Shane AL, Weintrub PS. Treatment of pediatric refractory coccidioidomycosis with combination voriconazole and caspofungin: a retrospective case series. Clin Infect Dis. 2013;56:1573–8. 78. Hartmann K, Lloret A, Pennisi MG, Ferrer L, Addie D, Belak S, et al. Aspergillosis in cats: ABCD guidelines on prevention and management. J Feline Med Surg. 2013;15:605–10. 79. Barrs VR, Halliday C, Martin P, Wilson B, Krockenberger M, Gunew M, et al. 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Smith LN, Hoffman SB. A case series of unilateral orbital aspergillosis in three cats and treatment with voriconazole. Vet Ophthalmol. 2010;13:190–203. 92. Kano R, Itamoto K, Okuda M, Inokuma H, Hasegawa A, Balajee SA. Isolation of Aspergillus udagawae from a fatal case of feline orbital aspergillosis. Mycoses. 2008;51:360–1. 93. Talbot JJ, Kidd SE, Martin P, Beatty JA, Barrs VR. Azole resistance in canine and feline isolates of Aspergillus fumigatus. Comp Immunol Microbiol Infect Dis. 2015;42:37–41. 94. Barrs VR, van Doorn TM, Houbraken J, Kidd SE, Martin P, Pinheiro MD, et al. Aspergillus felis sp nov., an emerging agent of invasive aspergillosis in humans, cats, and dogs. PLoS One. 2013;8:e64871. 95. Miller RI. Nodular granulomatous fungal skin diseases of cats in the United Kingdom: a retrospective review. Vet Dermatol. 2010;21:130–5. 96. Leperlier D, Vallefuoco R, Laloy E, Debeaupuits J, Thibaud PD, Crespeau FL, et al. Fungal rhinosinusitis caused by Scedosporium apiospermum in a cat. J Feline Med Surg. 2010;12:967–71. 97. Pawloski DR, Brunker JD, Singh K, Sutton DA. Pulmonary Paecilomyces lilacinus infection in a cat. J Am Anim Hosp Assoc. 2010;46:197–202. 98. Kluger EK, Della Torre PK, Martin P, Krockenberger MB, Malik R. Concurrent Fusarium chlamydosporum and Microsphaeropsis arundinis infections in a cat. J Feline Med Surg. 2004;6:271–7. 99. Sugahara G, Kiuchi A, Usui R, Usui R, Mineshige T, Kamiie J, et al. Granulomatous pododermatitis in the digits caused by Fusarium proliferatum in a cat. J Vet Med Sci. 2014;76: 435–8. 100. Binder DR, Sugrue JE, Herring IP. Acremonium keratomycosis in a cat. Vet Ophthalmol. 2011;14(Suppl 1):111–6. 101. Muir D, Martin P, Kendall K, Malik R. Invasive hyphomycotic rhinitis in a cat due to Metarhizium anisopliae. Med Mycol. 1998;36:51–4. 102. Overy DP, Martin C, Muckle A, Lund L, Wood J, Hanna P. Cutaneous Phaeohyphomycosis caused by Exophiala attenuata in a domestic cat. Mycopathologia. 2015;180:281–7. 103. Tennant K, Patterson-Kane J, Boag AK, Rycroft AN. Nasal mycosis in two cats caused by Alternaria species. Vet Rec. 2004;155:368–70. 104. Bostock DE, Coloe PJ, Castellani A. Phaeohyphomycosis caused by Exophiala jeanselmei in a domestic cat. J Comp Pathol. 1982;92:479. 105. Dion WM, Pukay BP, Bundza A. Feline Cutaneous phaeohyphomycosis caused by Phialophora verrucosa. Can Vet J. 1982;23:48–9. 106. Sisk DB, Chandler FW. Phaeohyphomycosis and cryptococcosis in a cat. Vet Pathol. 1982;19:554–6. 107. Kettlewell P, McGinnis MR, Wilkinson GT. Phaeohyphomycosis caused by Exophiala spinifera in two cats. J Med Vet Mycol. 1989;27:257–64. 108. Nuttal W, Woodgyer A, Butler S. Phaeohyphomycosis caused by Exophiala jeanselmei in a domestic cat. N Z Vet J. 1990;38:123. 109. Abramo F, Bastelli F, Nardoni S, Mancianti F. Feline cutaneous phaeohyphomycosis due to Cladophyalophora bantiana. 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Antimicrob Agents Chemother. 2006;50:2533–6. VetBooks.ir 328 J. D. Lemetayer and J. E. Sykes 139. Diekema DJ, Messer SA, Hollis RJ, Jones RN, Pfaller MA. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol. 2003;41:3623–6. 140. Ndiritu CG, Enos LR. Adverse reactions to drugs in a veterinary hospital. J Am Vet Med Assoc. 1977;171:335–9. 141. Wang A, Ding HZ, Liu YM, Gao Y, Zeng ZL. Single dose pharmacokinetics of terbinafine in cats. J Feline Med Surg. 2012;14:540–4. VetBooks.ir Sporothrichosis Hock Siew Han Abstract Sporothrix schenckii is currently recognized as a species complex consisting of Sporothrix brasiliensis, Sporothrix schenckii sensu stricto, Sporothrix globosa, and Sporothrix luriei. Due to divergent evolutionary process, each species possesses different virulence profiles, that allow it to thrive and persist in its niche. Currently the disease in cats is primarily caused by S. brasiliensis, S. schenckii sensu stricto and S. globosa, with cat fights and direct inoculation of the agent in the skin as the main mode of disease transmission. Expression of putative virulence factors, such as adhesins, ergosterol peroxide, melanin, proteases, extracellular vesicles and thermotolerance, determines the clinical manifestation in the feline patient, with thermotolerant S. brasiliensis exhibiting the highest pathogenicity, followed by S. schenckii sensu stricto, and S. globosa. Their ability to produce biofilm is documented, but their clinical significance remains to be elucidated. Despite comprehensive descriptions of the pathogenicity of the agent and of the disease, its prognosis remains guarded to poor, due to issues pertaining to cost, protracted treatment course, zoonotic potential and low susceptibility of some strains to antifungals. Introduction Sporothrix schenckii complex (also called S. schenckii sensu lato) causes a chronic, granulomatous, cutaneous or subcutaneous infection, mainly occurring in humans and cats. It has been recognised as an important cause of zoonotic subcutaneous mycosis since its description by Dr. Benjamin Schenk in 1896 [1]. H. S. Han (*) The Animal Clinic, Singapore © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_15 329 VetBooks.ir 330 H. S. Han As a thermally dimorphic fungus, Sporothrix schenckii sensu lato exists as saprophyte in plant debris or decaying organic soil matter in its asexual filamentous form (25–30 °C). With favourable temperature and environment (35–37 °C), it phase transitions into its yeast form, and complete growth inhibition is achieved at 40 °C, with no sexual reproduction observed to date [2]. This characteristic underpins the epidemiology of clinical sporotrichosis where historically, the most common route of infection was reported to be the inoculation of conidia into broken skin via contaminated soil during horticultural activities. It is only in recent times that cats were perceived to be an important risk factor and disease propagators [3–7]. Etiologic Agent Sporothrix schenckii is currently recognized as a species complex consisting of Sporothrix brasiliensis, Sporothrix schenckii sensu stricto, Sporothrix globosa, and Sporothrix luriei (Clinical clade) based on DNA sequencing, with each species having its own distinct virulence profiles and geographical distribution [8, 9]. S. brasiliensis, S. s. sensu stricto and S. globosa, in order of virulence, are the main species identified to cause pathology in cats [9]. S. brasiliensis, currently regionally restricted to Brazil, is characterised by its inherent thermotolerability which is responsible for causing systemic spread. This species was identified as the main cause of sporotrichosis epidemics in Rio de Janeiro and Sao Paolo, alongside S. s. sensu stricto and S. globosa [10–12]. S. s. sensu stricto is the second most pathogenic species with a worldwide distribution, especially in tropical or subtropical regions, with reports from the Americas, Africa, Australia and Asia. Zhou and colleagues demonstrated genetic diversity within this single species by subdividing S. s. sensu stricto into clinical clade C (most commonly isolated from Americas and Asia) and D (most commonly isolated from Americas and Africa), based on its internal transcribed spacer (ITS) [13]. The recent identification of a single clonal strain of S. s. sensu stricto clinical clade D from Malaysia (instead of the commonly isolated clinical clade C in Asia) suggests that this species is constantly evolving, with the ability to undergo a process of selection and subsequent population expansion, depending on local environmental or host selection pressure [14, 15]. S. globosa is commonly identified as the species responsible for sporotrichosis mainly in Asia and Europe, but is a rare cause in the Americas and Africa [11, 13, 16–20]. Exept S. pallida, Environmental clade associated sporothrix species such as S.brunneoviolacea, S. lignivora, S. chilensis and S. mexicana (Sporothrix pallida complex) have not been reported to cause disease in the feline patient at the time of writing [21]. These species are rare agents of sporotrichosis and normally causes low virulence, opportunistic infections from traumatic inoculation of fungus from soil into host tissue. This is in contrast to sporothrix species within the Clinical clade that is transmitted from animals. Sporothrichosis 331 VetBooks.ir Pathogenesis Upon inoculation, the expression of putative virulence factors, such as adhesins, ergosterol peroxide, melanin, proteases, extracellular vesicles (EV) and thermotolerance, determines the pathogenicity and clinical presentation of sporotrichosis in the feline patient [22, 23]. The expression of adhesins and a 70 kDa glycoprotein (Gp70) on the cell wall mediates adhesion of the fungus to fibronectin, type II collagen and laminin in the host [24]. Upon invasion, the fungal cell wall composed of glucans, galactomannans, rhamnomannans, chitin, glycoprotein, glycolipids and melanin provides the ability to survive within host tissues and aids evasion from host innate immune response [25– 27]. Melanin production in both mycelial and yeast form shields against a broad range of toxic insults. Melanin reduces susceptibility to antifungals and enzymatic degradation, and confers protection against oxygen nitrogen free radicals, macrophagic and neutrophilic phagocytosis [28]. The fungus readily produces ergosterol peroxide and proteinases (Proteinase 1 and 2), which allow it to evade phagocytosis and host immune response [29, 30]. EV (exosomes, microvesicles and apoptotic bodies) are membranous compartments composed of lipid bilayers, released by all living cells to the extracellular medium, that contain cargos of lipids (neutral glycolipids, sterols and phospholipids), polysaccharides (glucuronoxylomannan, alpha-galactosyl epitopes), proteins (lipases, proteases, urease, phosphatase) and nucleic acids (RNA) [31]. These cargos represent virulence factors that contribute to drug resistance, facilitate cell invasion and are eventually recognized by the innate immune system. EV contribution to fungal virulence was described in Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Malassezia sympodialis, Candida albicans and, recently, also in Sporothrix brasiliensis [32–39]. Specifically, the EV cargos of Sporothrix brasiliensis, such as cell wall glucanase and heat shock proteins, were shown to increase phagocytosis but not pathogen elimination, stimulate cytokine production (IL-12p40 and TNFα) and favour the establishment of the fungus in the skin [38, 40, 41]. Current proteomic analyses revealed that 27% of EV proteins in S. brasiliensis and 35% in S. schenckii remain to be characterized, including the identification of their assigned biological process [38]. Thermotolerance, the ability of a fungus to grow or not at 37 °C, is another important virulence factor that has been identified in Sporothrix spp. Isolates that are able to grow at 35 °C but not at 37 °C in humans cause fixed cutaneous lesions, but those that grow at 37 °C (a close approximation to human and animal core body temperature) produce disseminated and extracutaneous lesions. Pathogenic thermotolerant species, such as S. brasiliensis have the ability to produce disseminated disease, compared to non-thermotolerant, less pathogenic species such as S. globosa. S. s. sensu stricto displays variable thermotolerability [14]. VetBooks.ir 332 H. S. Han The ability of Sporothrix schenckii complex to produce biofilm has recently been documented, and an early report suggests that biofilm production alters the fungus sensitivity to antifungals, however, the full extent of its clinical significance has yet to be elucidated [42]. Both innate and adaptive immune responses play important roles in the prevention of disease progression. The first contact between fungal pathogen associated molecular pattern (PAMPs) and host pattern recognition receptors (PPRs) is mediated by toll-like-receptors (TLR)-4 and TLR-2 [43, 44]. During the initiation of infection, these receptors recognize lipid extracts from yeast cells that lead to an increased production of tumour necrosis factor alpha (TNF-alpha), interleukin (IL)10 and nitric oxide (NO). While NO demonstrates antifungal activity in vitro, in vivo it is associated with immunosuppression during the initial and the terminal stages of the infection, due to its ability to increase apoptosis of immune cells [45]. The role of NO in the infection was also documented in histoplasmosis by Histoplasma capsulatum and paracoccidioidomycosis by Paracoccidioides brasiliensis [46, 47]. Yeast cells are also able to activate the antibody-dependent classical and alternative complement pathways [48, 49]. The main antigen recognized by antibodies is a 70 kDa cell wall glycoprotein, named Gp70 [50]. This protein plays a crucial role in fungal opsonisation, allowing macrophages to phagocytose and the production of pro-inflammatory cytokines [51]. Nevertheless, the cornerstone for an effective fungal eradication is based on an effectively coordinated innate and adaptive immune response (humoral and cell mediated) [52]. Recently, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome was shown to be critical to link the innate immune response to the adaptive arm, contributing to effective protection against this infection by promoting the production of pro-IL1β [53]. Fungal interaction with dendritic cells drives a mixed Th1/Th17 immune response that activates macrophages, neutrophils and CD4+ T cells, that release IFN-gamma, IL-12 and TNF-alpha that ultimately culminates in the reduction of pathogen burden [54, 55]. Clinical Signs Feline sporotrichosis occurs most commonly in young adult, free roaming intact male cats and is associated with fighting, with no known breed predisposition [4]. In the human patient, clinical signs of sporotrichosis may be classified into 3 forms: fixed cutaneous, lympho-cutaneous and disseminated forms, depending on the pathogenicity of the fungal species and the status of host immunity (Fig. 1). Such clear and distinct categorisation of clinical forms does not apply to cats and thus is seldom used. In cats, chronic non-healing lesions such as nodules, ulcers and crusts are commonly found on the head, especially at the bridge of the nose (Fig. 2), on the distal limbs and tail base region (Fig. 3) and on the pinnae (Fig. 4). The majority of lesions occur in cooler regions of the host body such as at the nasal passages and ear tips. VetBooks.ir Sporothrichosis Fig. 1 A human patient manifesting lymphocutaneous sporotrichosis after being bitten by a cat with sporotrichosis (nodule at base of thumb). Due to the lack of thermotolerability of the infectious agent, the lesion did not progress beyond the arm Fig. 2 Classical presentation of feline sporotrichosis: chronic non-healing wounds affecting the bridge of the nose Fig. 3 Chronic nonhealing wounds affecting the paws and the tail 333 334 b VetBooks.ir a H. S. Han Fig. 4 (a and b) Concave and convex aspects, respectively, of the pinna of a cat with sporotrichosis presenting numerous ulcerated nodules If nasal passages are affected, extracutaneous signs such as sneezing, dyspnoea and respiratory distress are commonly reported in tandem with cutaneous manifestations [5]. Cutaneous screwworm myiasis as secondary infestation was recently reported [56]. The fatal disseminated form of the disease is associated with S. brasiliensis infection. Co-infection with either feline immunodeficiency virus (FIV) or feline leukaemia virus (FeLV) has no significant effect on the clinical manifestations or on the prognosis of the disease [57]. Diagnosis A definitive diagnosis of feline sporotrichosis requires the isolation and identification of the agent in culture. The species identification can be obtained by morphologic studies and physiologic phenotyping, as well as by polymerase chain reaction targeting the calmodulin gene [5]. At 25–30°, the fungus exists in its mycelial form and is seen as small and white or pale orange to orange-grey colonies with no cottony aerial hyphae. Later, the colony becomes black, moist, wrinkled, leathery or velvety with narrow white borders (Fig. 5). Some colonies are however black from the onset. At 35–37°, yeast colonies are cream or tan, smooth and yeast-like [2]. Cytologically, yeasts are found in abundance from cutaneous impression smears. They are located intra- and extracellularly, in pleomorphic shapes, ranging from VetBooks.ir Sporothrichosis 335 Fig. 5 In its mature mycelial form the fungi becomes black, moist, wrinkled, leathery or velvety with narrow white borders Fig. 6 Cytologically, the yeasts are found in abundance intra- and extracellularly in pleomorphic shapes, ranging from the classical cigar-shaped to round or oval, measuring 3–5 μm in diameter with a thin, clear halo around a pale blue cytoplasm (Diff Quick, 1000×) the classical cigar-shaped to round or oval bodies, measuring 3–5 μm in diameter with a thin, clear halo around a pale-blue cytoplasm (Fig. 6) [58]. The sensitivity of cytology to detect Sporothrix yeasts in the feline patient is estimated to range from 79% to 84.9% [59, 60]. On histology, a diffuse pyogranulomatous inflammation with large foci of necrosis is seen throughout the superficial and deep dermis, sometimes extending to the subcutis. There are abundant round to cigar-shaped organisms, 3–10 μm in length and 1–2 μm in diameter, seen both free and within macrophages. Commonly, organisms in cytoplasm of macrophages create large clear pockets full of yeast due to poorly visualized yeast cell wall (Fig. 7) [61]. Periodic acid of Schiff (PAS) stain may also be utilized to visualize yeasts as magenta stained organism on histological preparation. Other diagnostic techniques such as serology (enzyme-linked immunosorbent assay, ELISA) and polymerase chain reaction (PCR) may also be used for the diagnosis [62, 63]. VetBooks.ir 336 H. S. Han Fig. 7 On histology there are abundant round to cigar-shaped organisms, 3–10 μm in length to 1–2 μm in diameter seen both free and within macrophages. Organisms in cytoplasm of macrophages create large clear pockets full of yeasts due to poorly visualized yeast cell wall Treatment Treatment of feline sporotrichosis requires several months and must be continued for at least 1 month beyond clinical cure. Luckily, despite a protracted treatment course, it is current understanding that the fungus does not develop resistance during treatment [14]. Due to the high cost of treatment, high risk of therapeutic side effects and of zoonosis and existence of low susceptibility strains, feline sporotrichosis carries a guarded to poor prognosis. Currently, potassium iodide, azolic antifungals (ketoconazole, itraconazole), amphotericin B, terbinafine, local heat therapy, cryosurgery and surgical resection have all been documented as treatment options in the feline patient. Potassium iodide has traditionally been the treatment of choice, either in its saturated form (saturated salt of potassium iodide, SSKI) or in its powder form re-packaged into capsules. Dosages range from 10 to 20 mg/kg every 24 hours [64, 65]. The powder form re-packaged into capsules is favoured over SSKI for the feline patient, due to the latter’s tendency to cause hypersalivation. From a report of 48 cats receiving potassium iodide, 23 (47.9%) patients achieved clinical cure with treatment failure in 18 cats (37.5%), two reported deaths (4.2%) and treatment period averaging from 4 to 5 months. The most commonly observed side effects were hyporexia, lethargy, weight loss, vomiting, diarrhoea plus an increase in the liver enzyme alanine transaminase. No signs of iodism (lacrimation, salivation, coughing, facial swelling, tachycardia) nor thyroid hormone abnormalities were observed in this study [64]. Due to its low cost, potassium iodide is still often used either singularly or in conjunction with azole antifungals to treat feline sporotrichosis [65]. VetBooks.ir Sporothrichosis 337 Imidazoles such as ketoconazole and itraconazole currently represent the cornerstone therapy for feline sporotrichosis. Itraconazole is favoured over ketoconazole as the latter is commonly associated with a higher rate of side effects, such a vomiting, hepatic dysfunction and altered cortisol metabolism. Itraconazole at 5–10 mg/ kg has been used successfully to treat feline sporotrichosis, with a maximum plasma concentration of 0.7 ± 0.14 mg/L achieved after a 5 mg/kg oral dosing [66]. Based on the updated Clinical and Laboratory Standards Institute (CLSI) reference method for broth dilution antifungal susceptibility testing of filamentous fungi (document M38-A2), the minimum inhibitory concentration (MIC) of antifungals against S. brasiliensis, S. s sensu stricto and S. globosa is presented in Table 1 [14, 19, 20, 67, 68]. Itraconazole may be the treatment of choice but there are isolates with MIC above 4 mg/L, the putative breakpoint for this antifungal agent. This variability in MIC values may reflect the extensive divergent evolutionary process within the Sporotrix complex, where each species developed its own repertoire of virulence factors allowing thriving and persisting in its niche. Clinically, this is reflected by the fact that some cases of feline sporotrichosis are refractory to treatment and thus protocols based on higher dosages of itraconazole and/or its combination with other antifungals have been explored to treat these refractory cases [65, 69]. Sporothrix schenckii sensu lato generally displays low susceptibility towards fluconazole and exhibits species-dependent susceptibility towards terbinafine and amphotericin B (Table 1). Despite reports of successful treatment of human sporotrichosis with terbinafine, results are still inconclusive for the feline patient [70, 71]. The recent description of the protective effects of pyomelanin and eumelanin, synthesized by S. brasiliensis and S. s. sensu stricto, against the antifungal terbinafine may partially explain why in vitro results do not always correlate with in vivo responses when patients are treated with this drug [72]. The administration of amphotericin B is associated with toxicity, high cost and side effects, such as localized sterile abscess formation from intralesional injections [5]. It is interesting to note that Sporothrix spp. displays variable susceptibility towards antifungals rarely used in veterinary medicine such as micafungin, 5-flucytosine and even posaconazole, highlighting the importance of susceptibility testing [14, 20, 68]. Resolving granulomas are visually and tactile-wise indistinguishable from normal adjacent healthy skin under normal room lighting, and may be better visualized when held against a bright light source (Fig. 8). Treatment should be continued for 1 month beyond the resolution of all granulomas. Localized heat therapy is based on the fact that the fungus does not grow at temperatures above 40 °C. This treatment modality, however, is associated with issues of practicality and perhaps welfare concerns in its application on animals and has not been pursued as a feasible treatment option in the feline patient. Cryosurgery, used in conjunction with itraconazole has been used successfully to treat and cure 11 of 13 cats with sporotrichosis, with treatment lasting 3–16 months and a median of 8 months [73]. Surgical resection is possible for localized singular lesions but unpractical for generalized, disseminated forms. S. brasiliensis S. s. sensu stricto S. globosa 40 9 61 5 32 23 Japan Brazil Iran Brazil Brazil 4 n 29 9 4 Malaysia Iran Origin Japan subgroup I Japan subgroup II Brazil Itraconazole 0.5–4 0.25–2 0.83 (0.06–16) 8 (1 -> 16) 1.3 (0.5–4) 0.5–1 0.42 (0.03–16) 0.76 (0.25–2) 2 0.36 (0.06–2) Not tested 56.7 (16–128) >128 57.7 (8–128) >64 Fluconazole >128 >128 53.8 (16–128) >64 32 -> 64 >256 2 1.06 (0.03–2) 3.03 (1–8) 1.2 1.03 (0.2–4) Amphotericin B 1–4 2–4 1 (0.2–4) 5.66 (4–8) Not tested Terbinafine Not tested Not tested 0.03 (0.01–0.06) 1.68 (1–2) 2.85 (1–8) Not tested 0.05 (0.01–0.50) 0.38 (0.13–1) 0.1 0.06 (0.01–0.50) [68] [67] [19] [20] [67] [14] [19] References [20] [20] [67] Table 1 All results are expressed in mg/L and based on the Clinical and Laboratory Standards Institute (CLSI) reference method for broth dilution antifungal susceptibility testing of filamentous fungi document M38-A2 (2008) in mycelial phase VetBooks.ir 338 H. S. Han Sporothrichosis b VetBooks.ir a 339 Fig. 8 The author utilizes a bright light source to evaluate and ascertain cure. (a) A resolving granulomatous reaction at the left ear tip, tactile and visually indistinguishable from adjacent normal tissue but is visualized with a bright light source. (b) Same patient after cure with complete resolution of granuloma Conclusion The prognosis of feline sporotrichosis remains guarded to poor due to cost, protracted treatment course, risk of zoonosis and low susceptibility of some strains. Despite the fact that antifungal susceptibility testing provides essential guidance for the treatment, its lack of commercial availability and validated breakpoints remains a stumbling block in the treatment of this disease. Unfortunately, the current repertoire of veterinary antifungals classes are inadequate to address the issue of fungal low fungal susceptibility. References 1. Schenck BR. 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Negrini Tde C, Ferreira LS, Alegranci P, Arthur RA, Sundfeld PP, Maia DC, et al. Role of TLR-2 and fungal surface antigen on innate immune response against Sporothrix schenckii. Immuno Invest. 2013;42:36–48. 45. Fernandes KS, Neto EH, Brito MM, Silva JS, Cunha FQ, Barja-Fidalgo C. Detrimental role of endogenous nitric oxide in host defense againsts Sporothrix schenckii. Immunology. 2008;123:469–79. VetBooks.ir 342 H. S. Han 46. Brummer E, Division DA. Antifungal mechanism of activated murine bronchoalveolar or peritoneal macrophages for Histoplasma capsulatum. Clin Exp Immunol. 1995;102:65–70. 47. Bocca L, Hayashi EE, Pinheiro G, Furlanetto B, Campanelli P, Cunha FQ, et al. Treatment of Paracoccidioides brasiliensis-infected mice with a nitric oxide inhibitor prevents the failure of cell-mediated immune response. J Immunol. 1998;161:3056–63. 48. Torinuki W, Tagami H. Complement activation by Sporothrix schenckii. 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De Souza CP, Lucas R, Ramadinha RH, Pires TB. Cryosurgery in association with itraconazole for the treatment of feline sporotrichosis. J Feline Med Surg. 2016;18:137–43. VetBooks.ir Malassezia Michelle L. Piccione and Karen A. Moriello Abstract Malassezia dermatitis/overgrowth is a superficial fungal (yeast) skin disease of cats. It has most often been reported in association with underlying hypersensitivity skin diseases, metabolic diseases, neoplasia and paraneoplastic syndromes. Common clinical signs include dark waxy debris associated with otitis externa, scaling, black waxy nail bed debris (paronychia), variable pruritus, erythema, and exudative dermatitis especially when complicated by bacterial pyoderma. The disease is most commonly diagnosed by cytological examination of the skin. Malassezia pachydermatis is the primary species isolated from cats; however, other lipid-dependent species can be isolated. Itraconazole is the treatment of choice along with topical antifungal shampoo therapy or leave-on antifungal products. Recurrent Malassezia dermatitis is a clinical sign of an underlying trigger, most of which are not life threatening. In cats with severe widespread disease, especially those with erythema, alopecia and/or marked scaling, Malassezia species overgrowth could be a clinical sign of systemic disease warranting a thorough systemic evaluation. Introduction Malassezia are yeast organisms and are part of the normal cutaneous microflora of humans and animals, including cats [1]. At the time of writing, at least 16 different human and animal species have been isolated. A review of the literature revealed a wide range of species isolated from cats but molecular diagnostics are reclassifying M. L. Piccione (*) · K. A. Moriello School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA e-mail: mpiccione@wisc.edu; karen.moriello@wisc.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_16 345 VetBooks.ir 346 M. L. Piccione and K. A. Moriello some of these species [2]. Several recent studies reconfirmed that the most commonly isolated species from cats are M. pachydermatis, M. furfur, M. nana, and M. sympodialis [3–6]. For the purposes of this chapter, the term “Malassezia dermatitis” and “Malassezia overgrowth” are synonymous and the former will be used for simplicity. Malassezia spp. dermatitis is increasingly being recognized as a complicating factor in many feline skin diseases, often in association with bacterial overgrowth. The goal of this chapter is to review the scientific literature available on Malassezia dermatitis in cats and summarize the key aspects of clinical signs, diagnosis, and treatment. Etiology and Pathogenesis of Feline Malassezia Biological Characteristics The genus Malassezia are lipophilic yeast, are part of the cutaneous microflora of warm-blooded animals and tend to colonize skin rich in sebaceous glands. Malassezia belong to the basidiomycetous yeasts. They are characterized by a multilayered cell wall and reproduce by unilateral budding [7]. Bottle-shaped yeast may be globose, ovoid, or cylindrical. Buds form on a narrow or wide base [7]. Currently, the genus Malassezia includes 16 species, of which 15 are lipiddependent and are most frequently recovered from humans, ruminants, and horses (Malassezia furfur, M. globosa, M. obtusa, M. restricta, M. slooffiae, M. sympodialis, M. dermatis, M. nana, M. japonica, M. yamatoensis, M. equina, M. caprae and M. cuniculi, M. brasiliensis, M. psittaci) [8]. The only non-lipid-dependent species, M. pachydermatis, is commonly recovered from cats and dogs [8]. With the exception of M. pachydermatis, the lipophilic yeast requires supplementation of long chain fatty acids in culture medium; utilizing the lipids is a source of carbon for survival [8]. Pathogenesis M. pachydermatis is considered a nonpathogenic, commensal organism that can become an opportunistic pathogen when the environmental factors are appropriate and/or the host’s defense mechanism fails. Factors involved in maintaining the balance of skin microflora include temperature, hydration, chemical constituents (sweat, sebum, and saliva) and pH [9]. When these factors are altered, Malassezia can overgrow and act as a pathogen on the skin of cats, inducing an inflammatory response. M. pachydermatis has been shown to adhere to human keratinocyte cells and keratinocytes respond by releasing pro-inflammatory mediators as a defense mechanism [10]. Humoral and cell-mediated responses to Malassezia have been documented and anything that interferes with or blunts these responses can result in overgrowth [11]. Malassezia 347 VetBooks.ir Prevalence There are many studies investigating the carriage of Malassezia in healthy cats, cats with skin disease, in specific cat breeds, on various skin sites and in association with other diseases. It is important to keep in mind that reported studies used different methodologies (i.e., culture, cytology, combination of culture and cytology) making direct comparisons difficult. In one study comparing 10 domestic short-haired (DSH) cats with no history of skin disease (controls) and 32 Sphynx cats, Malassezia was not isolated from the skin of control cats [12]. In Sphynx cats, it was isolated from 26 of 32 cats of which 5 were reported to have greasy skin (Fig. 1). There were 73 isolates of Malassezia, of which 69 were M. pachydermatis. Interestingly, Malassezia was not isolated from the ears of any of the 42 cats. In another study, carriage was compared between several groups of cats: 10 normal DSH, 33 Cornish Rex cats (5 normal, 28 with seborrheic skin disease), and 30 Devon Rex cats (21 normal and 9 with seborrheic skin disease) [13]. Malassezia was isolated in 5 of 10 normal cats, 5 of 15 Cornish Rex cats, and 27 of 30 Devon Rex cats. When normal and diseased cat data was pooled, M. pachydermatis was isolated from 70% of cats with seborrheic skin disease and only 17% of cats with normal skin. In this study, 121 of 141 isolates were M. pachydermatis. The prevalence of Malassezia in the ear canal of cats is an area of interest, since otitis is a common problem in cats (Chapter, Otitis) (Fig. 2). In one study, Malassezia species were isolated from the ear canal of 63 of 99 (63.6%) cats with otitis and 12 of 52 (23%) normal cats [14]. In this study, M. pachydermatis, M. globosa, and M. furfur were the most common isolates. In another study, Malassezia was isolated from 9 of 17 cats with otitis externa and in 16 of 51 cats without otitis [15]. Again, M. pachydermatis, M. globosa, and M. furfur were the most common isolates. In Fig. 1 Sphynx cat with seborrheic dermatitis and yeast overgrowth. This cat was very pruritic and yeast organisms were found on cytology from the papular eruption shown. The cat was diagnosed with environmental allergies VetBooks.ir 348 M. L. Piccione and K. A. Moriello Fig. 2 Ear of cat with yeast otitis. This is the pinna of a cat with hypersensitivity dermatitis. The cat has extremely pruritic ears and it responded well to topical steroid treatment Fig. 3 Nail fold of a cat with Malassezia dermatitis. The owner reported that this cat licked and chewed at the paws and nail fold area. The lesions resolved with topical and systemic antifungal treatment. The cat had concurrent diabetes mellitus yet another study involving normal and affected cats, Malassezia was isolated in 7 of 25 and 15 of 20 cats [16]. Again, M. pachydermatis and M. sympodialis were the most common isolates. Another interesting site that has been investigated in cats is the nail fold (Fig. 3). In one study, yeast were isolated from the claw fold of 26 of 29 Devon Rex cats [17]. In another study, Malassezia was found in 28 of 46 nail fold samplings from cats [3]. Yeast were found in all 15 Devon Rex cats, 10 DSH cats, and 3 Persian cats. Malassezia are also commonly found in the nail folds of Sphynx cats [4]. The facial fold of Persian cats has also been investigated for Malassezia dermatitis [18]. This breed is well known to have facial fold dermatitis which is often idiopathic in origin. In one clinical case series, 13 Persian cats with idiopathic facial fold dermatitis were investigated and Malassezia dermatitis was found in 6 of 13 cats. There was an incomplete response to treatment, suggesting Malassezia was more of a complicating factor than a cause. VetBooks.ir Malassezia 349 Prevalence studies show some common trends. First, Malassezia can be found on healthy cats but it is not common. Carriage is more common in cat breeds with genetically associated follicular dysplasia (Devon Rex, Cornish Rex, and Sphynx cat breeds). Interestingly, although Cornish Rex and Devon Rex cats share similar coat characteristics, the frequency and population of Malassezia isolated are different. The degree of colonization may be associated with the Devon Rex cat’s predisposition to development of seborrheic dermatitis. Malassezia can be isolated from cats with and without otitis externa and from the nail folds of cats, particularly those with seborrheic or allergic skin disease. Finally, M. pachydermatis is the most common Malassezia isolate from cats. Malassezia and Concurrent Diseases Malassezia overgrowth/dermatitis is a common complication of skin diseases in other species and a similar picture is starting to emerge in cats. Hypersensitivity skin disease is common in cats and the role of Malassezia dermatitis is increasingly being recognized (Fig. 4). In one study of 18 cats with hypersensitivity dermatitis, Malassezia dermatitis was found in all cats [19]. Sixteen cats showed marked reduction in pruritus after treatment. This suggests Malassezia overgrowth may be a contributing factor in some cats with hypersensitivity dermatitis. Not all cats with hypersensitivity skin disease have Malassezia dermatitis. A molecular study on fungal microbiota of allergic cats (n = 8) found Malassezia in only 21% of 54 samples from the 8 allergic cats [20]. A study of aural microflora in healthy cats (n = 20) compared with allergic cats (n = 15) and cats with systemic disease (n = 15) found that Malassezia colonization was more common in cats with hypersensitivity dermatitis and systemically ill cats compared to healthy cats [21]. In another study, Malassezia was more commonly isolated from retroviral positive cats than retroviral negative cats [22]. Although the cats were healthy, possibly retroviral infections interfered with the innate immune response. When the frequency of isolation of Malassezia on the skin of cats with Fig. 4 This cat had hypersensitivity dermatitis and recurrent areas of eosinophilic dermatitis. Cytology revealed concurrent bacterial and Malassezia dermatitis. Lesions resolved with concurrent antibacterial and antifungal therapy VetBooks.ir 350 M. L. Piccione and K. A. Moriello diabetes mellitus (n = 16), hyperthyroidism (n = 20, and neoplasia were compared (n = 8) to normal cats (n = 10), no difference was found [23]. There is increasing evidence that Malassezia dermatitis may be associated with paraneoplastic alopecia and/or be a cutaneous sign of systemic disease. In the above study, Malassezia was isolated from 9 sites in one cat with feline paraneoplastic syndrome and pancreatic adenocarcinoma [23]. In another case report, marked exfoliative dermatitis and yeast overgrowth was found in a cat with thymoma (Figs. 5 and 6) and, interestingly, there was complete resolution of clinical signs after complete surgical tumor resection [24]. One case report described a 13-year-old DSH cat with a history of progressively worsening paraneoplastic alopecia along with Malassezia overgrowth. Post-mortem results revealed a pancreatic adenocarcinoma with hepatic metastases [25]. In a retrospective study evaluating skin biopsy specimens from cats, 15 specimens contained large numbers of Malassezia organisms Fig. 5 This is a 13-yearold cat that presented with marked exfoliative dermatitis with severe Malassezia dermatitis found on cytology. The cat was systemically ill. Imaging revealed a thymoma Fig. 6 This is a close-up view of the marked exfoliation on the skin of the cat in Fig. 5. Note marked erythema and large sheets of shed keratinocytes. This appearance of scales is highly suggestive of feline exfoliative dermatitis due to an underlying medical problem which may or may not be associated with a thymoma VetBooks.ir Malassezia 351 in the epidermis or follicular infundibulum [26]. When clinical data was evaluated, 11 of 15 cats had acute onset of multifocal to generalized skin lesions. All 10 cats were euthanized and one died of metastatic carcinoma of the liver 2 months after the onset of clinical signs. Clinical Signs There are no pathognomonic clinical signs for Malassezia dermatitis in cats. Clinical signs reported and/or commonly noted by the authors are summarized in Box 1 and chapter images. Concurrent bacterial overgrowth is common. Scaling and an unkempt coat (Fig. 8) is a common finding and often Malassezia is found on cytology. Many cats with Malassezia dermatitis due to poor grooming will respond to coat hygiene and topical therapy alone. Nail bed involvement may vary in clinical appearance, it is usually brown black (Fig. 3) and may appear as marked seborrheic accumulations. Box 1: Clinical Signs of Malassezia Dermatitis/Overgrowth • • • • • • • • • • • • • Lesions can be generalized or localized Pruritus varies from none to marked Erythema Diffuse seborrhea that can be dry and/or oily Increased scaling Hairs pierced by scales and follicular casts Traumatic alopecia Hyperpigmentation characterized by brown waxy exudate Follicular plugging on ventral abdomen, especially around nipples Brown to reddish brown discoloration of nails Waxy debris under the nail folds Brown waxy debris adherent to lip folds Chin acne Malassezia otitis • • • • Increased ceruminous debris Erythema of ear canal Swelling and narrowing of canal Pruritus of pinna and/or canal VetBooks.ir 352 M. L. Piccione and K. A. Moriello Fig. 7 Cat with Malassezia and bacterial overgrowth. Note the erythema, eruptions, and scaling Fig. 8 Malassezia dermatitis in a cat with an unkempt coat Diagnosis The diagnosis of Malassezia dermatitis is based the identification of organism in light of a compatible/plausible history and clinical signs and a good response to antifungal treatment. Cytology Cytological examination of the skin is the single best technique for investigating whether or not Malassezia are present. There are no cytological criteria for VetBooks.ir Malassezia 353 determining the “normal number” of Malassezia organisms present on the skin of cats. The presence or absence of organisms can only be interpreted in light of the cat’s clinical signs. The organisms are much larger than bacteria and can vary in size from 2–4 μm by 3 to 7 μm. Skin cytology samples can be obtained using a clear acetate tape which allows for sampling in difficult areas, e.g., facial, interdigital, or nail folds. A clear piece of tape is pressed to the skin, the tape is then stained using in-house cytology stains (e.g., Diff Quik). It is important to avoid the fixative step and to stain the tape by holding with forceps, tweezers, or the authors’ favorite tool, household clothes pins. Affixing unstained tape to a glass slide and then staining the slide results in poor staining and increased artifacts, and should be avoided. To make a proper preparation, put a drop of immersion oil on a glass slide, then mount a thoroughly dry stained piece of tape over the oil, and then examine it microscopically. For oil immersion, (recommended), a drop of immersion oil can be placed directly over the tape. Glass slide samples are the optimum tool to use when sampling the skin. To obtain the best possible sample, place the glass slide over the target area, gently lift the skin and squeeze the skin between two fingers. This will markedly increase the cellularity of the sample. Ears are best sampled with a cotton tip applicator. Nail beds are best sampled by gently scraping debris from under the claw fold using a skin scraping spatula, not a scalpel blade, and then smearing it onto a glass slide. In all cases, it is important to NOT heat fix slides as this will cause artifacts and/or damage other cells on the slide. It has been shown that increasing the number of dips in solution II (basophilic, blue) is all that is needed to improve visualization of yeast organisms [27, 28]. The authors routinely examine slides at 4× to find a cellular area, 10× and then 100×. Malassezia organisms are variable in size and may be seen easily on the slide or adherent to skin keratinocytes (Figs. 9 and 10). Fig. 9 Note the large number of Malassezia organisms in this ear cytology. There are peanut- and ovoid-shaped organisms. Some of the organisms have not stained as deeply basophilic and this is common in samples from ear cytology VetBooks.ir 354 M. L. Piccione and K. A. Moriello Fig. 10 Note the large number of Malassezia organisms adherent to skin cells. This sample was obtained from a cat with exfoliative dermatitis. Note the concurrent bacteria in this sample Fungal Culture It is rare to need to culture this organism for diagnosis in clinical cases. If there is a need, e.g., suspected antifungal resistance, for research or if there is need to identify the species, there are two important things to remember. First, if using a culture swab to culture the skin, moisten the swab with the transport medium and aggressively rub the swab over a large area of the skin while rotating the head of the swab 360°. In the authors’ experience, dry swab cultures of small areas are inadequate. If available, contact plate cultures are preferable. Secondly, it is common to isolate several different species from cats. It is important to inform the laboratory that both lipid-independent and lipid-dependent species are of clinical interest. M. pachydermatis is unique in that it grows well in Sabouraud dextrose agar at 32 °C to 37 °C without lipid supplementation; however, lipid-dependent Malassezia species will not grow on Sabouraud dextrose agar. Modified Dixon Agar and Leeming medium support growth of all Malassezia species. Due to the presence of lipid-dependent yeasts on the skin of cats, the use of lipid-supplemented media, especially the modified Dixon’s medium or Leeming medium, is required [8, 29, 30]. PCR PCR is not used in the routine diagnosis of Malassezia dermatitis in cats. Culture- based methods do not always allow species-specific identification and, if this is necessary, polymerase chain reaction (PCR) is a viable option. PCR uses laboratory methods that amplify DNA from a sample, even directly from skin or from culture with high accuracy and efficiency [31]. Recent findings show that the multiplex- real-time PCR was highly effective in identifying Malassezia species from animal and human samples [32]. Malassezia 355 VetBooks.ir Histopathology and Skin Biopsy Skin biopsy is not routinely used to diagnose Malassezia dermatitis in cats. If the cat is otherwise healthy and yeast are noted on the skin biopsy, their presence is most likely due to the underlying skin disease, e.g., hypersensitivity disease or primary disorder of keratinization. However, if the cat is ill and has marked skin lesions, the presence of Malassezia organism should be interpreted as a sign of systemic illness and a thorough medical evaluation pursued. Histological sections reporting Malassezia yeasts often note their presence in the stratum corneum of the epidermis or follicular infundibulum [26]. In cases of severe exfoliation, they may be reported in areas of mild to severe orthokeratotic to parakeratotic hyperkeratosis [26]. Treatment Treatment of Malassezia dermatitis in cats is individualized and depends on the severity of clinical signs and potential underlying cause. If the underlying cause is not identified and treated, Malassezia dermatitis will not resolve. If the underlying disease is chronic, e.g., hypersensitivity dermatitis, the owner should be warned that disease flares will cause relapses of Malassezia dermatitis. Topical Therapy The major obstacle to topical therapy for Malassezia dermatitis in cats is what the cat and owner can tolerate. Ideally, topical therapy is the treatment of choice. Attention to coat hygiene is important if there is matting or retained hairs. If the cat will tolerate bathing, the topical shampoos of choice are miconazole/chlorhexidine, ketoconazole/chlorhexidine, or climbazole/chlorhexidine combinations once or twice weekly. The authors have found it very helpful for owners to understand that Malassezia dermatitis is commonly associated with bacterial overgrowth, so combination products are the best choice. If the cat is otherwise healthy but has generalized lesions, whole body bathing is recommended. Given that this may not be possible, other options include the use of leave-on mousse products with the above ingredients. If lesions are focal, these combination products can be applied to just the affected areas. It is important to remember that grooming activities of cats put them at greater risk of adverse reactions to topical products. Systemic Antifungal Therapy Oral antifungal therapy is indicated if the topical therapy is impractical or ineffective. The oral antifungal of choice is itraconazole (Itrafungol, Elanco Animal Health). It is labelled for use in cats at 5 mg/kg orally once daily on an alternating VetBooks.ir 356 M. L. Piccione and K. A. Moriello week on/week off treatment schedule for dermatophytosis [33]. Itraconazole is generally well tolerated in cats and safe at this dose. The most common side effects reported were hypersalivation, decreased appetite, vomiting and diarrhea [33]. It is important to stress to clients that compounded itraconazole should not be used as there is strong evidence that it is not bioavailable [34]. The efficacy of oral itraconazole for treatment of Malassezia dermatitis was reported in two studies. In a retrospective study, 15 cats received 5 to 10 mg/kg itraconazole (Itrafungol/Janssen), administered orally once daily as the sole therapy [35]. Affected cats had either localized (n = 8) or generalized lesions (n = 7). Twelve of the cats had concurrent otitis externa. Itraconazole was effective in all cats with no reported side effects. In another study, pulse therapy (week on/week off) itraconazole was used to treat Malassezia dermatitis in 6 Devon Rex cats with concurrent seborrheic dermatitis [36]. There was a marked improvement in clinical signs with a reduction of inflammation and pruritus. Yeast Otitis Malassezia is a common cause of otitis externa in cats (Chapter, Otitis). It is most common in cats with hypersensitivity dermatitis (Fig. 2). Immediate treatment may include systemic itraconazole if there are large numbers of yeasts present and pruritus is severe. However, in most cases Malassezia otitis can be managed with weekly ear cleaning and topical application of an otic antifungal/glucocorticoid product. Long-term management of Malassezia otitis externa can be done successfully with once or twice weekly application of otic steroids. The authors frequently compound equal portions of injectable dexamethasone ear drops in saline or propylene glycol for the owner to apply. This avoids the unnecessary use of antimicrobials when the primary need is just an anti-inflammatory action. Zoonotic Implications Malassezia organisms are found on both people and animals. Malassezia pachydermatis is not a normal commensal organism. However, since cats can be colonized by both lipid-independent and lipid-dependent organisms, it is important for veterinary health care workers to practice good hand hygiene when handling cats and to remind owners to do the same. Conclusion Feline Malassezia dermatitis is a superficial fungal skin disease that can present with a wide range of clinical signs. Clinical signs are caused by overgrowth of normal body flora, and concurrent overgrowth of bacteria is common. Malassezia dermatitis is commonly associated with chronic skin diseases such as hypersensitivity VetBooks.ir Malassezia 357 disorders, seborrhea, and underlying metabolic diseases that can trigger changes in the skin immune system. Devon Rex cats appear particularly susceptible to both Malassezia colonization and M. pachydermatis associated seborrheic dermatitis, without evidence of systemic disease. Cytological examination is the most useful technique for assessment of the density of Malassezia yeasts on the skin surface. Additionally, contact-plate fungal cultures also provide a convenient technique for isolation and quantification of yeast colonies. PCR allows for rapid identification and speciation of samples analyzed as well. M. pachydermatis is the main species identified in cats, but lipid-dependent species, particularly in the claw folds, can also be found. Itraconazole is the systemic drug of choice along with concurrent topical therapy. Although rare, the finding of Malassezia dermatitis in cats with widespread skin lesions should prompt the clinician to consider whether or not this is an early marker of systemic disease. References 1. Theelen B, Cafarchia C, Gaitanis G, et al. Malassezia ecology, pathophysiology, and treatment. Med Mycol. 2018;56:S10–25. 2. Cabañes FJ. Malassezia yeasts: how many species infect humans and animals? PLoS Pathog. 2014;10:e1003892. 3. Colombo S, Nardoni S, Cornegliani L, et al. Prevalence of Malassezia spp. yeasts in feline nail folds: a cytological and mycological study. Vet Dermatol. 2007;18:278–83. 4. Volk AV, Belyavin CE, Varjonen K, et al. Malassezia pachydermatis and M nana predominate amongst the cutaneous mycobiota of Sphynx cats. J Feline Med Surg. 2010;12:917–22. 5. Bond R, Howell S, Haywood P, et al. Isolation of Malassezia sympodialis and Malassezia globosa from healthy pet cats. Vet Rec. 1997;141:200–1. 6. Crespo M, Abarca M, Cabanes F. Otitis externa associated with Malassezia sympodialis in two cats. J Clin Microbiol. 2000;38:1263–6. 7. Guillot J, Gueho E, Lesord M, et al. Identification of Malassezia species: a practical approach. J Mycol Med. 1996;6:103–10. 8. Böhmová E, Čonková E, Sihelská Z, et al. Diagnostics of Malassezia Species: a review. Folia Vet. 2018;62:19–29. 9. Tai-An C, Hill PB. The biology of Malassezia organisms and their ability to induce immune responses and skin disease. Vet Dermatol. 2005;16:4–26. 10. Buommino E, De Filippis A, Parisi A, et al. Innate immune response in human keratinocytes infected by a feline isolate of Malassezia pachydermatis. Vet Microbiol. 2013;163:90–6. 11. Sparber F, LeibundGut-Landmann S. Host responses to Malassezia spp. in the mammalian skin. Front Immunol. 2017;8:1614. 12. Åhman SE, Bergström KE. Cutaneous carriage of Malassezia species in healthy and seborrhoeic Sphynx cats and a comparison to carriage in Devon Rex cats. J Feline Med Surg. 2009;11:970–6. 13. Bond R, Stevens K, Perrins N, et al. Carriage of Malassezia spp. yeasts in Cornish Rex, Devon Rex and Domestic short-haired cats: a cross-sectional survey. Vet Dermatol. 2008;19:299–304. 14. Nardoni S, Mancianti F, Rum A, et al. Isolation of Malassezia species from healthy cats and cats with otitis. J Feline Med Surg. 2005;7:141–5. 15. Crespo M, Abarca M, Cabanes F. Occurrence of Malassezia spp. in the external ear canals of dogs and cats with and without otitis externa. Med Mycol. 2002;40:115–21. 16. Dizotti C, Coutinho S. Isolation of Malassezia pachydermatis and M. sympodialis from the external ear canal of cats with and without otitis externa. Acta Vet Hung. 2007;55:471–7. VetBooks.ir 358 M. L. Piccione and K. A. Moriello 17. Åhman S, Perrins N, Bond R. Carriage of Malassezia spp. yeasts in healthy and seborrhoeic Devon Rex cats. Sabouraudia. 2007;45:449–55. 18. Bond R, Curtis C, Ferguson E, et al. An idiopathic facial dermatitis of Persian cats. Vet Dermatol. 2000;11:35–41. 19. Ordeix L, Galeotti F, Scarampella F, et al. Malassezia spp. overgrowth in allergic cats. Vet Dermatol. 2007;18:316–23. 20. Meason-Smith C, Diesel A, Patterson AP, et al. Characterization of the cutaneous mycobiota in healthy and allergic cats using next generation sequencing. Vet Dermatol. 2017;28:71–e17. 21. Pressanti C, Drouet C, Cadiergues M-C. Comparative study of aural microflora in healthy cats, allergic cats and cats with systemic disease. J Feline Med Surg. 2014;16:992–6. 22. Sierra P, Guillot J, Jacob H, et al. Fungal flora on cutaneous and mucosal surfaces of cats infected with feline immunodeficiency virus or feline leukemia virus. Am J Vet Res. 2000;61:158–61. 23. Perrins N, Gaudiano F, Bond R. Carriage of Malassezia spp. yeasts in cats with diabetes mellitus, hyperthyroidism and neoplasia. Med Mycol. 2007;45:541–6. 24. Hljfftee Ma M-V, Curtis C, White R. Resolution of exfoliative dermatitis and Malassezia pachydermatis overgrowth in a cat after surgical thymoma resection. J Small Anim Pract. 1997;38:451–4. 25. Godfrey D. A case of feline paraneoplastic alopecia with secondary Malassezia associated dermatitis. J Small Anim Pract. 1998;39:394–6. 26. Mauldin EA, Morris DO, Goldschmidt MH. Retrospective study: the presence of Malassezia in feline skin biopsies. A clinicopathological study. Vet Dermatol. 2002;13:7–14. 27. Toma S, Cornegliani L, Persico P, et al. Comparison of 4 fixation and staining methods for the cytologic evaluation of ear canals with clinical evidence of ceruminous otitis externa. Vet Clin Pathol. 2006;35:194–8. 28. Griffin JS, Scott D, Erb H. Malassezia otitis externa in the dog: the effect of heat-fixing otic exudate for cytological analysis. J Veterinary Med Ser A. 2007;54:424–7. 29. Guillot J, Bond R. Malassezia pachydermatis: a review. Med Mycol. 1999;37:295–306. 30. Peano A, Pasquetti M, Tizzani P, et al. Methodological issues in antifungal susceptibility testing of Malassezia pachydermatis. J Fungi. 2017;3:37. 31. Vuran E, Karaarslan A, Karasartova D, et al. Identification of Malassezia species from pityriasis versicolor lesions with a new multiplex PCR method. Mycopathologia. 2014;177:41–9. 32. Ilahi A, Hadrich I, Neji S, et al. Real-time PCR identification of six Malassezia species. Curr Microbiol. 2017;74:671–7. 33. Puls C, Johnson A, Young K, et al. Efficacy of itraconazole oral solution using an alternating- week pulse therapy regimen for treatment of cats with experimental Microsporum canis infection. J Feline Med Surg. 2018;20:869–74. 34. Mawby DI, Whittemore JC, Fowler LE, et al. Comparison of absorption characteristics of oral reference and compounded itraconazole formulations in healthy cats. J Am Vet Med Assoc. 2018;252:195–200. 35. Bensignor E. Treatment of Malassezia overgrowth with itraconazole in 15 cats. Vet Rec. 2010;167:1011–2. 36. Åhman S, Perrins N, Bond R. Treatment of Malassezia pachydermatis-associated seborrhoeic dermatitis in Devon Rex cats with itraconazole–a pilot study. Vet Dermatol. 2007;18:171–4. VetBooks.ir Viral Diseases John S. Munday and Sylvie Wilhelm Abstract Viruses are becoming increasingly recognized as an important cause of feline skin disease. Diseases associated with viruses in cats include hyperplastic and neoplastic skin disease caused by papillomaviruses, erosive and ulcerative skin disease caused by herpesviruses and poxviruses, and skin lesions that develop as a part of a more generalized viral infection as is seen due to calicivirus infection. Skin disease may also be seen in cats infected by feline leukemia virus and feline infectious peritonitis virus. In this chapter, the etiology and epidemiology of infection by each of the viruses that cause feline skin disease are reviewed along with the clinical disease presentation, the histological lesions, and other appropriate diagnostic tests. Additionally, the expected clinical course of the diseases and the currently recommended therapies are described. Introduction Viruses have traditionally been thought to rarely cause skin disease in cats. However, research in the last 30 years has expanded both the number of viruses that cause feline skin disease and the types of skin lesions caused by these viral infections. Feline viral infections can be broadly subdivided into those that cause hyperplastic or neoplastic skin disease (papillomaviruses), those that cause cell lysis and generally self-resolving inflammatory disease (herpesvirus, poxvirus), and those that infrequently cause skin lesions as part of a more generalized viral infection J. S. Munday (*) Massey University, Palmerston North, New Zealand e-mail: j.munday@massey.ac.nz S. Wilhelm Vet Dermatology GmbH, Richterswil, Switzerland © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_17 359 VetBooks.ir 360 J. S. Munday and S. Wilhelm (calicivirus, feline leukemia virus, feline infectious peritonitis virus). While feline immunodeficiency virus is briefly discussed, it is currently uncertain whether or not this virus causes skin disease in cats. Papillomaviruses Papillomaviruses (PVs) are small, non-enveloped, circular double-stranded DNA viruses that typically infect stratified squamous epithelium. Their DNA contains seven open reading frames (ORFs), including five that code for the early (E) proteins and two that code for the late (L) proteins [1]. Their life cycle is dependent on the terminal differentiation, keratinization, and desquamation of epithelial cells, and feline PVs cause disease due to the ability of their E7 proteins to alter the normal growth and differentiation of these cells. Papillomaviruses are considered one of the oldest viral families and have co-evolved with their hosts over a long time. For this reason, the majority of PVs are species-specific and the overwhelming majority of PV infections are asymptomatic [2]. Papillomaviruses are classified by comparing the similarities of the L1 ORF [3]. Currently five PV types are recognized to infect cats, including Felis catus papillomavirus (FcaPV) type 1, which is classified in the Lambdapapillomavirus genus [4, 5]; FcaPV-2, which is classified in the Dyothetapapillomavirus genus [6]; and FcaPV-3, -4 and -5, which have not been fully classified, but will likely be grouped together in a novel feline PV genus [7–9]. Although most PV infections are asymptomatic, PVs were first proposed to be a cause of feline skin disease in 1990, when PV-induced cell changes were observed in a cutaneous plaque [10]. Since this time, the importance of PVs as a cause of skin disease has been increasingly recognized and PVs are currently thought to cause viral plaques/Bowenoid in situ carcinomas, a proportion of squamous cell carcinomas, feline sarcoids, a proportion of basal cell carcinomas and cutaneous viral papillomas [11]. Feline Viral Plaques/Bowenoid In Situ Carcinoma These lesions have traditionally been thought of as two separate skin diseases of cats. However, as viral plaques and Bowenoid in situ carcinomas (BISCs) share many histological features and transitional lesions between the two lesions are often visible [12], it appears these two lesions are different severities of the same process. Etiology and Epidemiology FcaPV-2 is thought to be the predominant cause of these lesions [13, 14]. Current evidence suggests most kittens are infected from the dam within the first few weeks of life [15]. Infection by FcaPV-2 is probably lifelong and often does not stimulate an antibody response [16]. As most cats are infected by FcaPV-2, but few develop viral plaques/BISCs, it appears that host factors are important in determining VetBooks.ir Viral Diseases 361 whether or not a cat will develop clinical disease. While immunosuppressed cats may be at increased risk of viral plaque/BISC development, many cats have been reported to develop lesions without any detectable immunosuppression, and the factors that predispose a cat to lesion development are largely unknown [17]. The early development and severe manifestation of viral plaques/BISCs in Devon Rex and Sphinx cats suggests a genetic susceptibility, although the basis of this susceptibility is unknown [18]. Viral plaques/BISCs have also been associated with infection by FcaPV-3 and FcaPV-5. Currently little is known about the epidemiology of these viruses. Clinical Presentation Viral plaques/BISCs most often develop between the ages of eight and 14 years, although they have been reported in cats as young as 7 months of age [12, 19]. Cats with viral plaques tend to be younger than those with BISCs, supporting the hypothesis that some viral plaques progress to BISCs. Viral plaques most often develop on the trunk, head, or neck although in advanced cases lesions can develop anywhere on the body. They are often multiple and small, generally less than 1 cm in diameter, scaly papules or plaques that may be either pigmented or nonpigmented and can be covered by thin crusts (Fig. 1). While BISCs can appear clinically very similar to viral plaques, they tend to be larger, more markedly raised, and can be ulcerated or covered by a serocellular crust or a thick layer of keratin (Fig. 2). The head, neck, and limbs are most commonly affected. Viral plaques and BISCs can develop within pigmented or nonpigmented, haired or nonhaired skin and neither lesion is typically painful or pruritic [12]. Histopathology and Diagnosis Histology of a viral plaque reveals a well-demarcated focus of mild epidermal hyperplasia. Cells retain their orderly maturation and no dysplasia is visible (Fig. 3). Histology of a BISC reveals a well-demarcated focus of marked epidermal Fig. 1 Feline viral plaque. Plaques most frequently appear as focal, slightly raised lesions around the face of cats. Feline viral plaques and Bowenoid in situ carcinomas appear to be different severities of the same disease process with viral plaques the milder form of the disease. (Courtesy of Dr. Sharon Marshall, Veterinary Associates, Hastings, New Zealand) J. S. Munday and S. Wilhelm VetBooks.ir 362 Fig. 2 Feline Bowenoid in situ carcinoma. As with viral plaques, these often develop on the head of cats. Compared to a viral plaque, Bowenoid in situ carcinomas are larger, more markedly raised, and covered by increased quantities of keratin. However, as viral plaques and Bowenoid in situ carcinomas represent different severities of the same disease process and there is no clear distinction between the two lesions. (Courtesy of Dr. Richard Malik, Centre for Veterinary Education, University of Sydney, Australia) Fig. 3 Feline viral plaque. Plaques appear as well-demarcated foci of mild to moderate epidermal hyperplasia. Little dysplasia is visible within the hyperplastic cells and orderly maturation of the cells is retained (HE, 200×) hyperplasia that can extend to involve follicular infundibula. The hyperplastic cells can form well-demarcated solid masses of basilar cells that bulge into the underlying dermis. Examination of deeper layers of the BISC reveals keratinocyte dysplasia with crowding of basal cells and cells with nuclei that are elongated vertically (windblown cells) [20]. Dyskeratosis is rarely visible within BISCs. Although significant atypia can be present, the cells remain confined by the basement membrane (Fig. 4). Viral replication can result in prominent PV-induced changes. However, keratinocyte dysplasia can prevent viral replication and PV-induced cell changes 363 VetBooks.ir Viral Diseases Fig. 4 Feline Bowenoid in situ carcinoma. Compared to the viral plaque, the hyperplasia is more marked with prominent involvement of follicular infundibula. There is moderate atypia within the cell population, but no penetration of the basement membrane. While papillomavirus-induced cell changes are prominent in this lesion, more advanced Bowenoid in situ carcinomas often contain little histological evidence of papillomavirus infection. (HE, 200×) Fig. 5 Feline viral plaque. Papillomavirus-induced cell changes include the presence of keratinocytes that have dark nuclei surrounded by a clear halo (koilocytes; arrows) as well as the presence of cells that contain increased quantities of grey-blue smudged cytoplasm (arrowheads; HE, 400×) are rare in larger more developed BISCs. PV-induced changes include the presence of large keratinocytes with clear or blue-grey granular cytoplasm and/or shrunken nuclei that are surrounded by a clear halo (koilocytes; Fig. 5) [17]. Eosinophilic intranuclear inclusions can be visible, although care has to be taken to differentiate these from nucleoli. Hyperplasia of cells deeper within follicles or hyperplasia of sebaceous glands may be visible in viral plaques/BISCs that are caused by FcaPV-3 or -5. Additionally, these lesions contain prominent basophilic cytoplasmic inclusions that are often flattened against the nucleus [8, 21]. If no PV-induced changes are visible, then differentiation from actinic in situ carcinoma (actinic keratosis) is VetBooks.ir 364 J. S. Munday and S. Wilhelm required. Features that support a BISC rather than an actinic lesion include the consistently altered nuclear polarity of the basal cells, the sharp demarcation between affected and normal epidermis, and the follicular involvement. In addition, actinic lesions will also often have solar elastosis visible in the underlying dermis. Immunohistochemistry can be used in cases in which histological differentiation between a Bowenoid and an actinic in situ carcinoma is problematic. Antibodies to detect PV antigen can be used. However, antigens are only produced during viral replication and it is rare to have immunohistochemical evidence of PV infection in a lesion that does not contain PV-induced cell changes [17]. Therefore, p16CDK2NA protein (p16) immunohistochemistry is recommended to investigate a PV etiology. The detection of a marked increase in p16 suggests a PV etiology because PVs cause cell dysregulation by mechanisms that consistently increase p16 (Fig. 6). In contrast, in actinic lesions, loss of cell regulation is caused by mechanisms that do not increase p16 [22]. When performing p16 immunohistochemistry it has to be remembered that only the G175-405 human p16 clone has been shown to cross-react with the feline p16 protein. As p53 immunostaining can be present in both actinic keratosis and BISCs, this will not be useful to differentiate between a Bowenoid and an actinic lesion [22]. Due to the frequency with which PVs asymptomatically infect skin, the detection of PV DNA in a lesion does not confirm a diagnosis of BISC or exclude a diagnosis of actinic in situ carcinoma. Treatment Viral plaques and BISCs can spontaneously resolve, persist without progressing, or slowly increase in size and number. In addition, all viral plaques/BISCs should be carefully monitored for progression to a SCC. Lesions in Devon Rex and Sphinx cats can rapidly progress to SCCs that have metastatic potential [18, 23]. Surgical excision of a viral plaque or BISC is expected to be curative, although additional lesions may subsequently develop at different locations. Imiquimod cream has been used to treat genital warts in people and has been suggested as a Fig. 6 Feline viral plaque. The use of antibodies against p16CDKN2A protein reveals intense nuclear and cytoplasmic immunostaining throughout the hyperplastic epidermis (Hematoxylin counterstain 400×) VetBooks.ir Viral Diseases 365 possible treatment. Imiquimod stimulates toll-like receptors and locally increases alpha interferon and tumor necrosis factor-α [24]. It is a topical therapy, usually applied three times per week for 8–16 weeks. In an uncontrolled study of 12 cats with BISCs, imiquimod resulted in partial resolution of at least one BISC in all 12 cats and complete remission of at least one BISC in 5 cats [25]. Side effects included local erythema and mild discomfort in five cats and potential signs of systemic toxicity, including neutropenia, elevated hepatic enzymes, anorexia, and weight loss were observed in two cats. While there is anecdotal evidence supporting the use of imiquimod cream, additional controlled studies are required to determine the efficacy and safety of this treatment. In humans, imiquimod has also been used to treat basal cell carcinomas and actinic lesions and this treatment does not appear to have a specific action against PV-induced lesions. Imiquimod is currently not recommended as a primary treatment for pre-neoplastic or neoplastic skin lesions in people, but may be effective if better established therapies are not available [26]. Likewise, in veterinary medicine, imiquimod has been used to treat viral and nonviral in situ carcinomas when other treatments were considered impractical, and investigation of a PV etiology may not be necessary prior to the use of imiquimod. Photodynamic therapy could be another treatment option as excellent response rates were recently reported, although there was no attempt in this study to differentiate between PV-induced and actinic in situ carcinomas [27]. Autologous vaccination has not been evaluated as a method of treating viral plaques/BISCs in cats. However, considering the immune response to a PV-induced lesion, this treatment modality is not expected to work. There is currently little evidence from any species that vaccination using autologous or virus-like particle vaccines has any significant efficacy in treating either PV-induced warts or preneoplastic lesions. Cutaneous Squamous Cell Carcinomas Squamous cell carcinomas (SCCs) are one of the most common skin neoplasms of cats and are a significant cause of morbidity and mortality (Chapter, Genetic Diseases for more information). While there can be no doubt that solar exposure is a significant cause of SCCs, there is evidence that PVs may also contribute to the development of some neoplasms. Evidence of a role of PVs includes the detection of FcaPV-2 DNA more frequently in cutaneous SCCs than in non-SCC skin samples [13]. Additionally, p16 immunostaining is visible within SCCs that contain PV DNA (Fig. 7) and SCCs that have p16 immunostaining demonstrate a different biological behavior, suggesting that they may have been caused by different carcinogenic pathways [28, 29]. Furthermore, FcaPV-2 RNA can be detected in a proportion of feline cutaneous SCCs and the proteins that are expressed by FcaPV-2 have been shown to have transforming properties in cell cultures [30, 31]. Overall current evidence suggests that PV infection causes most SCCs that develop in haired, pigmented skin and that PV infection, probably with UV light as a co-factor, could promote the development of between a third and a half of SCCs from nonhaired, nonpigmented VetBooks.ir 366 J. S. Munday and S. Wilhelm Fig. 7 Cutaneous squamous cell carcinoma. Immunostaining for p16CDKN2A protein is diffusely present within the nucleus and cytoplasm of the neoplastic cells. Papillomavirus DNA was amplified from this neoplasm using PCR (Hematoxylin counterstain 200×) skin [29]. However, as asymptomatic infection of the skin is extremely common in cats, it is currently impossible to definitively determine that role that FcaPV-2 plays in the development of cutaneous SCCs in cats. Feline Sarcoids Feline sarcoids are rare neoplasms in cats. They have also been called “fibropapillomas”; however, as fibropapillomas are considered hyperplastic rather than neoplastic lesions, the term “sarcoid” is preferred. Etiology and Epidemiology Bovine papillomavirus (BPV) type 14 has been consistently detected in feline sarcoids throughout the world [32–34], and infection by BPV-14 is thus considered to be the cause of this disease. BPV-14 is a Deltapapillomavirus that is most closely related to BPV-1 and -2, the causes of equine sarcoids [35]. The bovine deltapapillomaviruses have the unique ability to cause both self-resolving fibropapillomas in cattle and mesenchymal neoplasia in non-host species. Cows are commonly asymptomatically infected by BPV-14 [36], but BPV-14 was not detected in a large number of cutaneous and oral samples from cats [32]. This suggests that cats are probably dead-end hosts for the PV. It is currently unknown how BPV-14 is transmitted from cattle to cats. However, as this disease appears to be most common in cats that live in dairy barns, close contact with cattle appears to be necessary. It is also unknown whether any co-factors are required to allow BPV-14 to cause sarcoids. Evidence from horses suggests that mesenchymal cell proliferation may be important for equine sarcoid development and it is possible that cat fight wounds could be important in allowing introduction of the PV into the dermis and stimulating dermal mesenchymal proliferation. VetBooks.ir Viral Diseases 367 Fig. 8 Feline sarcoid. The mass protrudesi from close to the nasal philtrum of this cat. (Courtesy of Dr. William Miller, Cornell University College of Veterinary Medicine, Ithaca, New York) Clinical Presentation Feline sarcoids have only been reported in outdoor cats from rural environments and are most common in younger male cats. They develop as solitary or multiple slow- growing exophytic nonulcerated nodules most frequently around the face, especially involving the nasal philtrum and upper lip, although sarcoids have also been reported in distal limbs and tail (Fig. 8) [33]. There is some evidence to suggest feline sarcoids may also rarely develop within the oral cavity. Histopathology and Diagnosis A feline sarcoid should be suspected if an exophytic mass is observed around the mouth or nose of a young cat that has contact with cattle. Unlike typical PV infections of the skin, infection by the PV is confined to the dermis [34]. Therefore, the predominant histological feature of a sarcoid is a proliferation of moderately well-differentiated mesenchymal cells within the dermis (Fig. 9). The proliferative dermal mass is covered by hyperplastic epidermis that extends into the mesenchymal cells by the formation of prominent rete pegs [33, 34]. As the sarcoid does not support viral replication, sarcoids do not contain any PV-induced cell changes and immunohistochemistry will not reveal the presence of PV L1 antigen [34]. The amplification of BPV-14 DNA from the lesion confirms a diagnosis of feline sarcoid. Treatment While there are few clinical reports of feline sarcoids, these neoplasms appear to be locally infiltrative, but do not metastasize. In the authors’ experience, complete surgical excision is curative. However, as these lesions often develop around the nose and mouth, complete excision can be problematic and feline sarcoids often recur and show an increased growth rate after surgery. A cat with recurrent sarcoids was treated with topical imiquimod and intralesional cisplatin, but neither treatment appeared to alter the disease course and the cat was eventually euthanatized due to the local effects of the neoplasm [35]. VetBooks.ir 368 J. S. Munday and S. Wilhelm Fig. 9 Feline sarcoid. The neoplasm consists of moderately welldifferentiated fibroblasts that are covered by hyperplastic epidermis that forms prominent rete pegs (HE, 200×) Basal Cell Carcinomas These are rare neoplasms and only a limited number have been assessed for a PV etiology. However, a potential role of PVs in the development of feline basal cell carcinomas (BCCs) is supported by the observation that a proportion contain PV-induced changes [20, 37, 38]. Feline BCCs have not been reported to be caused by FcaPV-2. Instead feline BCCs have been associated with FcaPV-3 and a novel unclassified PV type [37, 38]. Cutaneous Papillomas In cats, FcaPV-1 causes oral papillomas that typically develop on the ventral surface of the tongue [39]. There are also sporadic reports of cutaneous viral papillomas. While cross-species infection by a human PV was originally suspected [40], this appears unlikely and spread of FcaPV-1 from the mouth to the skin of cats appears to be a more likely cause of these rare lesions. Herpesviruses Feline herpesvirus 1 is a double-stranded DNA Alphaherpesvirus that is a common cause of upper respiratory tract disease and conjunctivitis in younger cats. In 1971, it was reported that herpesvirus infection may also cause dermatitis in cats [41], and feline herpesvirus dermatitis is now recognized as a distinct, albeit rare, manifestation of herpesvirus infection. Etiology and Epidemiology The rate of feline herpesvirus 1 infection is difficult to determine as many cats are vaccinated against this virus at an early age. Infection of an unvaccinated cat VetBooks.ir Viral Diseases 369 typically results in clinical signs of upper respiratory disease, such as rhinotracheitis, and conjunctivitis. While the clinical signs usually resolve within a few days or weeks, the herpesvirus infection can become latent, especially in the trigeminal ganglia. These latent infections can become recrudescent if the cat becomes immunosuppressed. It is hypothesized that recrudescence of previous herpesviral infections within the cutaneous nerves could cause feline herpesvirus dermatitis [42]. Due to the likely role of immunosuppression in the pathogenesis of disease, cats receiving glucocorticoids may be predisposed to disease development [42]. Cats that are in a household with numerous other cats also appear to be at increased risk, although it is uncertain whether this is because the cats are immunosuppressed due to stress or because the cats are more likely to be exposed to herpesvirus [42]. Feline herpesvirus dermatitis has not been associated with infection by feline immunodeficiency virus or feline leukemia virus. While previous infection by herpesvirus is thought to be key in the pathogenesis of this disease, herpesvirus dermatitis has been reported in cats that have a good vaccination history and in cats that do not have a history of previous respiratory disease [43]. Clinical Presentation Herpesvirus dermatitis appears to be most common in cats around 5 years of age although this disease has been reported in cats 4 months to 17 years old [42, 44]. Most cats with herpesvirus dermatitis have lesions almost exclusively on the face with the dorsal muzzle to the bridge of the nose and periocular skin most frequently affected (Fig. 10). The lips can also be affected and, in rare cases, the lesions can become generalized over the body within a few days [42, 43, 45]. Lesions are typically erosions and ulcers that are covered by a thick serocellular crust and have been referred to as “ulcerative facial and nasal dermatitis and stomatitis syndrome.” The lesions tend to be roughly spherical and are often asymmetrical, but the development of symmetrical lesions does not exclude a herpesviral etiology. Regional lymphadenopathy can be present [45]. Oral lesions are only rarely reported in cats Fig. 10 Feline herpesviral dermatitis. This disease typically presents as multiple ulcerative lesions over the face, especially around the bridge of the nose. (Courtesy of Dr. Richard Malik, Centre for Veterinary Education, University of Sydney, Australia) VetBooks.ir 370 J. S. Munday and S. Wilhelm with herpesvirus dermatitis [45], and affected cats may or may not have active or historical evidence of respiratory disease. The skin lesions can be intensely pruritic, thus mimicking a wide range of possible differential diagnoses, especially in the absence of respiratory signs of disease. Depending on the localization of the lesions, differential diagnoses include allergic skin disease, calicivirus-associated dermatitis, autoimmune skin diseases, and erythema multiforme. Exfoliative erythema multiforme is a rare disease that has been reported to develop following infection by herpesvirus. Clinical signs include widespread scaling (exfoliation) in combination with alopecia. Accompanying systemic symptoms are possible and the lesions spontaneously resolve after clearance of the herpesvirus infection [46]. Histopathology and Diagnosis Histology of a lesion reveals full-thickness necrosis and loss of the epidermis. Underlying the areas of necrosis there are typically large numbers of inflammatory cells including a high proportion of eosinophils (Fig. 11). Necrosis of the epithelium can extend into the underlying follicular infundibula and adnexal glands. The epidermis adjacent to the areas of ulceration can be thickened and spongiotic. The lesions are covered by a marked serocellular crust that consists of degenerate inflammatory cells and fibrin. Careful examination of the intact epidermis adjacent to the necrosis, the follicles, and the adnexal glands may reveal the rare presence of intranuclear viral inclusions (Fig. 12). These are eosinophilic and surrounded by marginated nuclear material. Making a definitive diagnosis should not be problematic when inclusion bodies are present. However, in cases that do not have visible inclusions, additional techniques may be necessary. The most conclusive evidence supporting a diagnosis is the demonstration of herpesviral antigens within the lesions using immunohistochemistry [44]. The failure to amplify herpesviral DNA Fig. 11 Feline herpesviral dermatitis. The dermis contains large numbers of inflammatory cells including a large proportion of eosinophils (HE, 200×) VetBooks.ir Viral Diseases 371 Fig. 12 Feline herpesviral dermatitis. The epidermis adjacent to areas of ulceration is thickened and spongiotic with some cells containing eosinophilic intranuclear viral inclusions (arrows; HE, 400×) from a lesion using PCR excludes a diagnosis of herpesviral dermatitis. However, as DNA from latent or vaccinal herpesvirus infection or contamination from infected mucosa from grooming can be detected by PCR, this technique cannot be used to confirm a diagnosis of herpesviral dermatitis [47, 48]. Persico et al recently recommended that PCR can be used as a screening test for cases in which no viral inclusions are present, but immunohistochemistry was required to confirm a diagnosis of herpesviral dermatitis [48]. Treatment Herpesvirus dermatitis may resolve spontaneously, although as few untreated cats are described in the literature, the frequency of self-cure is uncertain. In some cats, supportive care such as treatment of secondary bacterial infection may result in resolution of the clinical signs of disease [43]. As immunosuppression could contribute to disease development, any immunosuppressive treatments should be discontinued. Small lesions can be surgically excised, although whether or not the lesions would have spontaneously resolved if they had been left is unknown [42]. While herpesviral skin disease in humans typically spontaneously resolves, numerous treatments have been developed to accelerate disease resolution. Some of these antiviral drugs may also be beneficial in cats, but they generally have complicated pharmacokinetics that may render them ineffective or toxic in cats and none has consistently been found to be safe and effective [49, 50]. Currently, famciclovir has the greatest amount of evidence supporting efficacy, both in naturally infected cats and in a placebo-controlled study of experimentally infected cats. The used dosages vary from 40 to 90 mg/kg once or twice daily to 125 mg/kg every 8 hrs [51, 52]. Topical “cold sore” creams, especially those containing pencivovir may also be beneficial and can be used with systemic famciclovir therapy (R. Malik, pers. comm). Interferons (IFNs), including IFNα and recombinant IFNω [53], have VetBooks.ir 372 J. S. Munday and S. Wilhelm also been suggested as potential treatments, although no controlled trials have been undertaken to assess their efficacy. Doses for IFNα again vary widely from 1MU/m2 subcutaneously three times a week to 0.01–1 MU/kg once daily for up to 3 weeks. Most often 30 units/day have been used [54]. The effectiveness of lysine supplementation is highly controversial and no clinical benefit has been proven [50, 55]. Poxvirus Poxviruses are large enveloped brick-shaped or oval linear double-stranded DNA viruses. Their DNA is 130–360 kb in length and encodes 130–320 proteins [56]. Most poxviruses are able to infect multiple species, and infection typically causes skin lesions due to the tropism of the viruses for epidermal keratinocytes. Skin disease due to poxviruses is rare in cats. Self-regressing proliferative skin disease due to infection with orf virus and pseudocowpox virus (both Parapoxviruses) has been sporadically reported in cats [57, 58]. However, the overwhelming majority of poxviral feline skin disease is caused by cowpox virus, an Orthopoxvirus, and the remainder of this section describes disease due to cowpox virus infection. In addition to the role of cowpox virus in diseases of cats, it also has to be noted that cats are important as a source of cowpox infection of humans. Etiology and Epidemiology Cowpox virus is a poor name for this virus as the reservoir hosts appear to be small mammals such as bank voles, short-tailed field voles, ground squirrels, and gerbils, with cattle, humans, and cats all only rarely infected [59]. The limited geographic distribution of the reservoir hosts explains why this disease is restricted to western Eurasia with the majority of clinical cases reported in the United Kingdom and Germany [59–61]. As cats are infected from a reservoir host during hunting, cowpox is limited to cats that have access to a rural environment, and increased numbers of cases are seen in autumn, due to increased hunting and greater numbers of reservoir host prey at this time [60, 62]. Skin disease is thought to develop after a reservoir host bites the cat. Systemic disease has also been reported, although it is uncertain if this results from inhalation of the virus or from systemic spread of the virus from an initial skin infection. While disease due to cowpox virus is rare in cats, exposure to the virus appears to be much more common, with antibodies against orthopoxviruses detected in 2–17% of cats from Western Europe [60, 63, 64]. Unsurprisingly, rates of exposure were highest in populations of cats that had outside access and from areas in which clinical cases had been reported [60]. As behavioral factors that predispose to cowpox exposure also predispose to infection with feline immunodeficiency virus (FIV), it is possibly unsurprising that cats with antibodies against orthopoxvirus were more likely to also have antibodies against FIV [64]. Viral Diseases 373 VetBooks.ir Clinical Presentation Lesions develop in younger to middle-aged cats that are able to come into contact with a reservoir host species [65]. As the lesions are initiated by a rodent bite, they typically start around the head or on the forelimbs. Lesions can subsequently spread to ears and paws, possibly by grooming and some cats can develop widespread lesions [62, 66]. The initial lesion is typically a single small raised ulcer covered by a serocellular crust at the site of inoculation by the rodent bite [62]. One to 3 weeks later, additional similar lesions may develop. These start as macules and small nodules that enlarge up to 1 cm in diameter (Fig. 13). They then become ulcerated, forming the typical crater-like skin lesion. These scab over and then gradually dry and exfoliate within 4–5 weeks. Pruritus is variable [67]. Up to 20% of cats may develop oral lesions, presumably due to the cat licking the skin lesions [66]. Cats that present with larger areas of dermal necrosis with extensive erythema, edema, abscessation, and cellulitis have also been reported (Fig. 14) [67, 68]. Whether this more severe presentation represents infection by a more virulent strain is uncertain. Cats may be transiently pyrexic and depressed during the viremic phase 1–3 weeks after infection, but most do not demonstrate signs of systemic disease on presentation [54, 66]. Rarely, cats may progress to develop signs of respiratory disease that can progress to a fatal pneumonia, although skin lesions are only variably present in cats that develop the respiratory form of cowpox disease. Pruritic lesions require differentiation from allergic skin diseases. Other differentials for nodular skin diseases in cats include infection by fungi or higher-order bacteria as well as neoplastic skin disease. Fig. 13 Feline cowpox dermatitis. This cat presented with numerous raised nodules on the forelimbs VetBooks.ir 374 J. S. Munday and S. Wilhelm Fig. 14 Feline cowpox dermatitis. The lesions in this cat progressed to erythema, edema, and cellulitis involving the paw Fig. 15 Feline cowpox dermatitis. Examination of the dermis reveals necrosis accompanied by large numbers of neutrophils. Epidermal cells are visible scattered within the inflammation. These cells show evidence of ballooning degeneration and some have prominent eosinophilic intracytoplasmic viral inclusions (arrows; HE, 200×) Histopathology and Diagnosis Due to the nonspecific nature of the skin lesions observed, biopsy and histology are required for diagnosis. Examination of a lesion reveals necrosis of the epidermis with ulceration. Examination of adjacent epidermis and within the epithelium of the follicles will usually reveal marked ballooning degeneration (Fig. 15). The ballooning change within these cells often demonstrates the presence of prominent intracytoplasmic poxvirus inclusions. These inclusions are eosinophilic and round to oval. The lesions are covered by a serocellular crust and the underlying dermis often contains significant neutrophilic inflammation. Serology or electron microscopy VetBooks.ir Viral Diseases 375 can be used to confirm orthopoxvirus infection, but not the orthopoxvirus type. Immunohistochemistry can be performed using monoclonal antibodies specific for cowpox virus [69]. Alternatively, virus isolation from a fresh biopsy or scab material or amplification of viral DNA using PCR will enable a precise diagnosis to be made [70]. Treatment Feline cowpox dermatitis has a good prognosis with most cases resolving spontaneously [66]. In cases with extensive or numerous lesions, supportive care may be required including the treatment of secondary bacterial infections. However, even cats with severe skin lesions most often make a full recovery, although scarring can occur [67]. The detection of serum antibodies against FIV does not influence the prognosis [66]. Why some cats develop respiratory disease is unknown. Treatment with immunosuppressive doses of corticosteroids is contraindicated as this may predispose to respiratory disease. While fatal pneumonia has been reported to develop in cats that were also infected by feline leukemia virus, feline immunodeficiency virus, or feline panleukopenia virus [66, 69], the role of these concurrent infections is uncertain and no underlying immunosuppression can be identified in most cases [61]. Cats with respiratory disease have a guarded prognosis and no specific treatments have been shown to be beneficial. Treatment with broad spectrum antibiotics to prevent secondary bacterial infection appears to be appropriate. Additionally, four cats with respiratory cowpox were treated with recombinant feline interferon omega. While two of the cats survived, it is currently impossible to determine whether interferon therapy is effective in the treatment of cowpox in cats [61]. The zoonotic potential of cowpox is an important consideration when formulating a treatment plan and infected cats are thought to cause around 50% of human cowpox infections [71]. Cowpox infection of people generally results in a transient, focal ulcerated lesion. However, life-threatening systemic cowpox virus infections can occur, particularly in immunosuppressed individuals [72], and in-clinic treatment may be most appropriate for cats owned by immunosuppressed clients. Calicivirus Feline calicivirus is a non-enveloped icosahedral single-stranded RNA virus that is classified in the Vesivirus genus. Feline calicivirus is well recognized to cause upper respiratory disease and oral ulcers in cats. Rarely, infection with caliciviruses can also cause skin lesions. 376 J. S. Munday and S. Wilhelm VetBooks.ir Etiology and Epidemiology Although only one calicivirus infects cats, these viruses are generally quick to mutate and different viral strains can express different antigens and show marked differences in virulence [73]. Feline calicivirus commonly infects cats, it is transferred via direct contact from infected cats and is shed in ocular, nasal, and oral secretions. Calicivirus is one of the most common viral pathogens of cats worldwide [73]. Skin lesions can develop in association with the more typical upper respiratory calicivirus infections. However, generalized severe skin lesions are generally restricted to cats that develop virulent systemic disease. This rare presentation of caliciviral disease usually develops as an outbreak, presumably as multiple cats are exposed to a recently developed virulent calicivirus strain. Outbreaks of virulent systemic disease have been reported involving veterinary hospitals and animal shelters in North America and Europe, although considering the widespread distribution of this virus, outbreaks in other countries appear likely to occur [74]. Calicivirus vaccines may reduce the severity of clinical signs of disease, but do not appear to be protective against infection by highly virulent calicivirus strains [75, 76]. Clinical Presentation Acute, nonvirulent, feline calicivirus infection is usually characterized by transient, self-limiting vesiculo-ulcerative lesions in the oral cavity (typically affecting the tongue), on the lips and nasal philtrum. Rarely ulceration can be detected on other body regions. Systemic signs, such as fever, depression, sneezing, conjunctivitis, oculonasal discharge, and arthropathy resulting in lameness that resolves in a few days (transient febrile limping syndrome) can also be observed [73]. Virulent systemic disease has been reported in cats from 8 weeks to 16 years of age, although adult cats may be more susceptible [74, 77, 78]. Cats that present with virulent systemic disease are unwell with fever, anorexia, lethargy, weakness, jaundice, or bloody diarrhea. Many cats will have oral ulcers [77]. Skin lesions include edema of the limbs and face with alopecia, ulcers and crusting lesions on the head (especially the lips, muzzle, and ears), and paw pads [73, 77]. Skin lesions have been reported less frequently on the abdomen and around the anus (Fig. 16) [76]. Two cats were reported to develop pustular skin disease due to calicivirus shortly after ovariohysterectomy. In these cats, lesions were restricted to the skin surrounding the wound. As both cats were also anorexic and depressed, it appears likely they both had systemic virulent disease. The presence of systemic disease was supported by the observation that one cat subsequently developed pleural effusion that necessitated euthanasia [79]. VetBooks.ir Viral Diseases 377 Fig. 16 Virulent systemic calicivirus infection. The cat has ulcers and crusting lesions on the ventral surface of the tail and surrounding the anus Fig. 17 Virulent systemic calicivirus infection. Histology reveals epidermal necrosis with ulceration. The ulcers are covered by a prominent serocellular crust (HE, 400×) Histopathology and Diagnosis Histology of the skin lesions reveals ballooning degeneration and necrosis of both surface and follicular epithelium with subsequent ulceration. Neutrophilic inflammation is often marked and ulcers are typically covered by a serocellular crust (Fig. 17) [77]. In cases in which the epidermis remains intact, intraepidermal and suprabasilar pustules may be visible [76]. Superficial dermal edema and vasculitis may also be detected. Diagnosis of systemic virulent calicivirus infection is unlikely to be made solely on histological examination of skin samples. Instead, the skin histology will be interpreted VetBooks.ir 378 J. S. Munday and S. Wilhelm along with the clinical evidence of severe systemic disease to make this diagnosis. A diagnosis of caliciviral dermatitis is supported by the demonstration of caliciviral antigens within the lesions using immunohistochemistry. The presence of viral nucleic acid can also be demonstrated using PCR, although since up to 30% of cats are carriers, the amplification of viral DNA should be interpreted with caution [54]. The detection of caliciviral nucleic acid from blood or lesions from a cat with clinical signs consistent with this disease is good evidence to support a diagnosis of caliciviral dermatitis [74]. Virus isolation and fluorescent antibody testing are also possible [73]. Treatment Treatment is supportive and commercially available antivirals do not inhibit replication of caliciviruses [62]. The prognosis is good for the acute nonvirulent systemic disease cases. Controlling secondary infections, regular cleaning of discharges and mucolytic drugs (e.g., bromhexine), or nebulization with saline are helpful. Often cats do not eat due to the oral ulcers, and placement of a feeding tube and enteral nutrition may be necessary in severe cases [54]. Intensive supportive treatment is recommended for cats with virulent systemic calicivirus infection, but even with such treatments mortality rates of 30–60% have been reported [77]. A feline calicivirus-specific antiviral phosphorodiamidate morpholino oligomer (PMO) was developed and used to treat kittens in three outbreaks of severe calicivirus disease. In this trial, 47 of 59 kittens that were treated with the PMO survived, but only three of 31 untreated cats survived [80]. The success of this experimental targeted therapy suggests that newer methods of treating calicivirus infections in cats may become available in the future. Feline Leukemia Virus Feline leukemia virus (FeLV) is a retrovirus that is classified within the Gammaretrovirus genus. Infection is most commonly spread in saliva by mutual grooming, but can also be spread by bites and through the milk. The role of FeLV in the development of some lymphomas is well established. The role of this virus in the development of feline skin disease is less defined, but four cutaneous manifestations of FeLV have been proposed. Immunosuppression As FeLV can cause significant immunodeficiency [81], it is possible that infection could predispose to increased opportunistic skin infections. However, there is little direct evidence supporting an increase in skin disease in cats due to FeLV infection and cats with FeLV rarely, if ever, initially present at a veterinarian due to recurrent or difficult to treat opportunistic skin infections [81]. Viral Diseases 379 VetBooks.ir Giant Cell Dermatosis This skin disease was first reported in six cats in 1994 and subsequently in an additional cat in 2005 [82, 83]. Evidence that the disease was caused by FeLV was the consistent detection of serum FeLV antigen and the presence of FeLV proteins in the lesions as demonstrated by immunohistochemistry. Interestingly, four of the cats had previously been vaccinated against FeLV and the authors speculated that some vaccines could contain infectious RNA that could result in the development of giant cell dermatosis [83]. To the authors’ knowledge, no additional cases of feline giant cell dermatosis have been reported. This suggests that this is a rare manifestation of FeLV infection in cats. Additionally, due to the small numbers that have been reported, it is not possible to definitively confirm that FeLV causes giant cell dermatosis in cats. Affected cats have been reported to present with variable clinical signs including multiple ulcers around the head, limbs, and paws [82], patchy alopecia and scaling starting on the dorsum, then progressing to become more generalized, or crusting skin lesions that were predominantly confined to the head and pinnae, but can also develop on the footpads and around the anus [83]. Pruritus was marked in many of the cats and concurrent gingivitis was frequently detected. Cats often presented with evidence of systemic disease, including pyrexia and anorexia. This disease can only be diagnosed by histology. Histology of a lesion reveals epidermal hyperplasia with the presence of prominent multinucleate keratinocytes that can contain up to 30 nuclei. Giant cells can be present within the surface epidermis, sebaceous glands, or in the follicular infundibula [82, 83]. Disorganization and keratinocyte atypia may be present within the affected epidermis. Inflammation may be prominent within the underlying dermis, especially in cases in which secondary bacterial infections are present. There are currently no treatments for this disease and all the cats that were reported to have this disease died shortly after diagnosis [82, 83]. Feline Paw Pad Cutaneous Horns Affected cats develop multiple horn-like lesions that typically involve multiple pads on multiple digits (Fig. 18). While these were initially associated with FeLV [84], subsequent studies have identified cats with horns that were not infected by FeLV [85, 86]. Whether FeLV infection is strictly necessary for disease development is currently uncertain. Cats present with multiple, elongated, conical or cylindrical masses involving the pads of multiple digits. The lesions consist almost entirely of keratin and so are typically grey, with a hard and dry texture. Histology reveals a well-demarcated column of dense pale orthokeratosis covering minimally to mildly hyperplastic epidermis (Fig. 19). Inflammation is typically minimal within the underlying dermis. Treatment is surgical excision although feline paw pad, and cutaneous horns often locally recur. As the lesions become bigger, they can develop fissures, which can result in secondary inflammation and pain. VetBooks.ir 380 J. S. Munday and S. Wilhelm Fig. 18 Feline paw pad cutaneous horn. Lesions are grey exophytic masses that often involve multiple paw pads Fig. 19 Feline paw pad cutaneous horn. The horns consist of a column of dense orthokeratosis overlying comparatively normal epidermis (HE, 50×) The location and appearance of these lesions typically allow clinical diagnosis to be made, although cutaneous horns that have developed secondary to Bowenoid in situ carcinomas or squamous cell carcinomas could require differentiation if they develop on the paw pad. Cutaneous Lymphoma Associations between FeLV and cutaneous lymphoma in cats have been inconsistently detected [87–89], and it currently appears that cats with FeLV infection are, at worst, at an only slightly increased risk of cutaneous lymphoma. Viral Diseases 381 VetBooks.ir Feline Infectious Peritonitis Virus Feline coronaviral-induced vasculitis (feline infectious peritonitis, FIP) rarely affects the skin. However, cats with FIP and skin lesions have sporadically been reported [90–92]. In all reported cases, the skin lesions developed late in the clinical course, in cats that also displayed more typical clinical signs such as pyrexia, lethargy, anorexia, or ocular lesions. The involvement of multiple cutaneous blood vessels results in the development of nonpruritic, nonpainful, raised papules over the neck and forelimbs or more generalized over the body. Histology reveals granulomatous vasculitis and immunohistochemistry can be used to confirm the presence of coronaviral antigens. Feline Immunodeficiency Virus Feline immunodeficiency virus (FIV) is a retrovirus within the Lentivirus genus. As the virus is typically spread by fighting, it is most common in free-roaming male cats. While experimental infection of cats can result in marked, fatal immunosuppression, natural infection of cats appears to be much less significant and the overall life-span of FIV-infected cats does not appear to be shorter than the life-span of uninfected cats [93]. Currently there is scant evidence that infection by FIV predisposes to feline skin disease [94]. While some initial cases of papillomaviral (PV) skin disease of cats were reported in cats with FIV, there have been no direct comparisons to determine if FIV-infected cats are disproportionately affected. Additionally, rates of PV infection were not higher in FIV-infected cats than in uninfected cats [95]. FIV has been associated with a mildly increased risk of lymphoma, although the precise role of the virus in neoplasm development is uncertain [96]. Cutaneous lymphoma has not been associated with FIV in cats. While an association between cutaneous SCCs and FIV infection was reported, this was suspected to be coincidental as higher rates of both SCCs and FIV infection are expected to be present in cats that spend significant amounts of time outside [97]. References 1. Munday JS, Pasavento P. Papillomaviridae and Polyomaviridae. In: NJ ML, Dubovi EJ, editors. Fenner’s Veterinary Virology. 5th ed. London: Academic Press; 2017. p. 229–43. 2. Munday JS. Bovine and human papillomaviruses: a comparative review. Vet Pathol. 2014;51:1063–75. 3. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology. 2004;324:17–27. 4. Tachezy R, Duson G, Rector A, et al. Cloning and genomic characterization of Felis domesticus papillomavirus type 1. Virology. 2002;301:313–21. VetBooks.ir 382 J. S. Munday and S. Wilhelm 5. Terai M, Burk RD. Felis domesticus papillomavirus, isolated from a skin lesion, is related to canine oral papillomavirus and contains a 1.3 kb non-coding region between the E2 and L2 open reading frames. J Gen Virol. 2002;83:2303–7. 6. Lange CE, Tobler K, Markau T, et al. Sequence and classification of FdPV2, a papillomavirus isolated from feline Bowenoid in situ carcinomas. Vet Microbiol. 2009;137:60–5. 7. Dunowska M, Munday JS, Laurie RE, et al. Genomic characterisation of Felis catus papillomavirus 4, a novel papillomavirus detected in the oral cavity of a domestic cat. Virus Genes. 2014;48:111–9. 8. Munday JS, Dittmer KE, Thomson NA, et al. Genomic characterisation of Felis catus papillomavirus type 5 with proposed classification within a new papillomavirus genus. Vet Microbiol. 2017;207:50–5. 9. Munday JS, Dunowska M, Hills SF, et al. Genomic characterization of Felis catus papillomavirus-3: a novel papillomavirus detected in a feline Bowenoid in situ carcinoma. Vet Microbiol. 2013;165:319–25. 10. Carney HC, England JJ, Hodgin EC, et al. Papillomavirus infection of aged Persian cats. J Vet Diagn Investig. 1990;2:294–9. 11. Munday JS, Thomson NA, Luff JA. Papillomaviruses in dogs and cats. Vet J. 2017;225:23–31. 12. Wilhelm S, Degorce-Rubiales F, Godson D, et al. Clinical, histological and immunohistochemical study of feline viral plaques and bowenoid in situ carcinomas. Vet Dermatol. 2006;17:424–31. 13. Munday JS, Kiupel M, French AF, et al. Amplification of papillomaviral DNA sequences from a high proportion of feline cutaneous in situ and invasive squamous cell carcinomas using a nested polymerase chain reaction. Vet Dermatol. 2008;19:259–63. 14. Munday JS, Peters-Kennedy J. Consistent detection of Felis domesticus papillomavirus 2 DNA sequences within feline viral plaques. J Vet Diagn Investig. 2010;22:946–9. 15. Thomson NA, Dunowska M, Munday JS. The use of quantitative PCR to detect Felis catus papillomavirus type 2 DNA from a high proportion of queens and their kittens. Vet Microbiol. 2015;175:211–7. 16. Geisseler M, Lange CE, Favrot C, et al. Geno- and seroprevalence of Felis domesticus Papillomavirus type 2 (FdPV2) in dermatologically healthy cats. BMC Vet Res. 2016;12:147. 17. Munday JS. Papillomaviruses in felids. Vet J. 2014;199:340–7. 18. Ravens PA, Vogelnest LJ, Tong LJ, et al. Papillomavirus-associated multicentric squamous cell carcinoma in situ in a cat: an unusually extensive and progressive case with subsequent metastasis. Vet Dermatol. 2013;24:642–5, e161–642. 19. Sundberg JP, Van Ranst M, Montali R, et al. Feline papillomas and papillomaviruses. Vet Pathol. 2000;37:1–10. 20. Gross TL, Ihrke PJ, Walder EJ, et al. Skin diseases of the dog and cat: clinical and histopathologic diagnosis. 2nd ed. Oxford: Blackwell Science; 2005. 21. Munday JS, Fairley R, Atkinson K. The detection of Felis catus papillomavirus 3 DNA in a feline bowenoid in situ carcinoma with novel histologic features and benign clinical behavior. J Vet Diagn Investig. 2016;28:612–5. 22. Munday JS, Aberdein D. Loss of retinoblastoma protein, but not p53, is associated with the presence of papillomaviral DNA in feline viral plaques, Bowenoid in situ carcinomas, and squamous cell carcinomas. Vet Pathol. 2012;49:538–45. 23. Munday JS, Benfell MW, French A, et al. Bowenoid in situ carcinomas in two Devon Rex cats: evidence of unusually aggressive neoplasm behaviour in this breed and detection of papillomaviral gene expression in primary and metastatic lesions. Vet Dermatol. 2016;27:215–e255. 24. Miller RL, Gerster JF, Owens ML, et al. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol. 1999;21:1–14. 25. Gill VL, Bergman PJ, Baer KE, et al. Use of imiquimod 5% cream (Aldara) in cats with multicentric squamous cell carcinoma in situ: 12 cases (2002–2005). Vet Comp Oncol. 2008;6:55–64. 26. Love W, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol. 2009;145:1431–8. VetBooks.ir Viral Diseases 383 27. Flickinger I, Gasymova E, Dietiker-Moretti S, et al. Evaluation of long-term outcome and prognostic factors of feline squamous cell carcinomas treated with photodynamic therapy using liposomal phosphorylated meta-tetra(hydroxylphenyl)chlorine. J Feline Med Surg 2018:1098612X17752196. 28. Munday JS, French AF, Gibson IR, et al. The presence of p16 CDKN2A protein immunostaining within feline nasal planum squamous cell carcinomas is associated with an increased survival time and the presence of papillomaviral DNA. Vet Pathol. 2013;50:269–73. 29. Munday JS, Gibson I, French AF. Papillomaviral DNA and increased p16CDKN2A protein are frequently present within feline cutaneous squamous cell carcinomas in ultraviolet-protected skin. Vet Dermatol. 2011;22:360–6. 30. Altamura G, Corteggio A, Pacini L, et al. Transforming properties of Felis catus papillomavirus type 2 E6 and E7 putative oncogenes in vitro and their transcriptional activity in feline squamous cell carcinoma in vivo. Virology. 2016;496:1–8. 31. Thomson NA, Munday JS, Dittmer KE. Frequent detection of transcriptionally active Felis catus papillomavirus 2 in feline cutaneous squamous cell carcinomas. J Gen Virol. 2016;97:1189–97. 32. Munday JS, Knight CG, Howe L. The same papillomavirus is present in feline sarcoids from North America and New Zealand but not in any non-sarcoid feline samples. J Vet Diagn Investig. 2010;22:97–100. 33. Schulman FY, Krafft AE, Janczewski T. Feline cutaneous fibropapillomas: clinicopathologic findings and association with papillomavirus infection. Vet Pathol. 2001;38:291–6. 34. Teifke JP, Kidney BA, Lohr CV, et al. Detection of papillomavirus-DNA in mesenchymal tumour cells and not in the hyperplastic epithelium of feline sarcoids. Vet Dermatol. 2003;14:47–56. 35. Munday JS, Thomson N, Dunowska M, et al. Genomic characterisation of the feline sarcoid- associated papillomavirus and proposed classification as Bos taurus papillomavirus type 14. Vet Microbiol. 2015;177:289–95. 36. Munday JS, Knight CG. Amplification of feline sarcoid-associated papillomavirus DNA sequences from bovine skin. Vet Dermatol. 2010;21:341–4. 37. Munday JS, Thomson NA, Henderson G, et al. Identification of Felis catus papillomavirus 3 in skin neoplasms from four cats. J Vet Diagn Investig. 2018;30:324–8. 38. Munday JS, French A, Thomson N. Detection of DNA sequences from a novel papillomavirus in a feline basal cell carcinoma. Vet Dermatol. 2017;28:236–e260. 39. Munday JS, Fairley RA, Mills H, et al. Oral papillomas associated with Felis catus papillomavirus type 1 in 2 domestic cats. Vet Pathol. 2015;52:1187–90. 40. Munday JS, Hanlon EM, Howe L, et al. Feline cutaneous viral papilloma associated with human papillomavirus type 9. Vet Pathol. 2007;44:924–7. 41. Johnson RP, Sabine M. The isolation of herpesviruses from skin ulcers in domestic cats. Vet Rec. 1971;89:360–2. 42. Hargis AM, Ginn PE. Feline herpesvirus 1-associated facial and nasal dermatitis and stomatitis in domestic cats. Vet Clin North Am Small Anim Pract. 1999;29:1281–90. 43. Sanchez MD, Goldschmidt MH, Mauldin EA. Herpesvirus dermatitis in two cats without facial lesions. Vet Dermatol. 2012;23:171–3, e135. 44. Lee M, Bosward KL, Norris JM. Immunohistological evaluation of feline herpesvirus-1 infection in feline eosinophilic dermatoses or stomatitis. J Feline Med Surg. 2010;12:72–9. 45. Suchy A, Bauder B, Gelbmann W, et al. Diagnosis of feline herpesvirus infection by immunohistochemistry, polymerase chain reaction, and in situ hybridization. J Vet Diagn Investig. 2000;12:186–91. 46. Prost C. P34 A case of exfoliative erythema multiforme associated with herpes virus 1 infection in a European cat. Vet Dermatol. 2004;15(Suppl. 1):41–69. 47. Holland JL, Outerbridge CA, Affolter VK, et al. Detection of feline herpesvirus 1 DNA in skin biopsy specimens from cats with or without dermatitis. J Am Vet Med Assoc. 2006;229:1442–6. 48. Persico P, Roccabianca P, Corona A, et al. Detection of feline herpes virus 1 via polymerase chain reaction and immunohistochemistry in cats with ulcerative facial dermatitis, VetBooks.ir 384 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. J. S. Munday and S. Wilhelm eosinophilic granuloma complex reaction patterns and mosquito bite hypersensitivity. Vet Dermatol. 2011;22:521–7. Lamm CG, Dean SL, Estrada MM, et al. Pathology in practice. Herpesviral dermatitis. J Am Vet Med Assoc. 2015;247:159–61. Maggs DJ. Antiviral therapy for feline herpesvirus infections. Vet Clin North Am Small Anim Pract. 2010;40:1055–62. Malik R, Lessels NS, Webb S, et al. Treatment of feline herpesvirus-1 associated disease in cats with famciclovir and related drugs. J Feline Med Surg. 2009;11:40–8. Thomasy SM, Lim CC, Reilly CM, et al. Evaluation of orally administered famciclovir in cats experimentally infected with feline herpesvirus type-1. Am J Vet Res. 2011;72:85–95. Gutzwiller MER, Brachelente C, Taglinger K, et al. Feline herpes dermatitis treated with interferon omega. Vet Dermatol. 2007;18:50–4. Nagata M, Rosenkrantz W. Cutaneous viral dermatoses in dogs and cats. Compendium. 2013;35:E1. Bol S, Bunnik EM. Lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats: a systematic review. BMC Vet Res. 2015;11:284. Delhon GA. Poxviridae. In: NJ ML, Dubovi EJ, editors. Fenner’s Veterinary Virology. 5th ed. London: Academic Press; 2017. p. 157–74. Fairley RA, Mercer AA, Copland CI, et al. Persistent pseudocowpox virus infection of the skin of a foot in a cat. NZ Vet J. 2013;61:242–3. Fairley RA, Whelan EM, Pesavento PA, et al. Recurrent localised cutaneous parapoxvirus infection in three cats. NZ Vet J. 2008;56:196–201. Chantrey J, Meyer H, Baxby D, et al. Cowpox: reservoir hosts and geographic range. Epidemiol Infect. 1999;122:455–60. Appl C, von Bomhard W, Hanczaruk M, et al. Feline cowpoxvirus infections in Germany: clinical and epidemiological aspects. Berl Munch Tierarztl Wochenschr. 2013;126:55–61. McInerney J, Papasouliotis K, Simpson K, et al. Pulmonary cowpox in cats: five cases. J Feline Med Surg. 2016;18:518–25. Mostl K, Addie D, Belak S, et al. Cowpox virus infection in cats: ABCD guidelines on prevention and management. J Feline Med Surg. 2013;15:557–9. Czerny CP, Wagner K, Gessler K, et al. A monoclonal blocking-ELISA for detection of orthopoxvirus antibodies in feline sera. Vet Microbiol. 1996;52:185–200. Tryland M, Sandvik T, Holtet L, et al. Antibodies to orthopoxvirus in domestic cats in Norway. Vet Rec. 1998;143:105–9. Breheny CR, Fox V, Tamborini A, et al. Novel characteristics identified in two cases of feline cowpox virus infection. JFMS Open Reports. 2017;3:2055116917717191. Bennett M, Gaskell CJ, Baxbyt D, et al. Feline cowpox virus infection. J Small Anim Pract. 1990;31:167–73. Godfrey DR, Blundell CJ, Essbauer S, et al. Unusual presentations of cowpox infection in cats. J Small Animal Pract. 2004;45:202–5. O’Halloran C, Del-Pozo J, Breheny C, et al. Unusual presentations of feline cowpox. Vet Record. 2016;179:442–3. Schaudien D, Meyer H, Grunwald D, et al. Concurrent infection of a cat with cowpox virus and feline parvovirus. J Comp Pathol. 2007;137:151–4. Jungwirth N, Puff C, Köster K, et al. Atypical cowpox virus infection in a series of cats. J Comp Pathol. 2018;158:71–6. Lawn R. Risk of cowpox to small animal practitioners. Vet Rec. 2010;166:631. Czerny CP, Eis-Hubinger AM, Mayr A, et al. Animal poxviruses transmitted from cat to man: current event with lethal end. Zentralbl Veterinarmed B. 1991;38:421–31. Radford AD, Addie D, Belák S, et al. Feline calicivirus infection: ABCD guidelines on prevention and management. J Feline Med Surg. 2009;11:556–64. Deschamps J-Y, Topie E, Roux F. Nosocomial feline calicivirus-associated virulent systemic disease in a veterinary emergency and critical care unit in France. JFMS Open Reports. 2015;1:2055116915621581. VetBooks.ir Viral Diseases 385 75. Pedersen NC, Elliott JB, Glasgow A, et al. An isolated epizootic of hemorrhagic-like fever in cats caused by a novel and highly virulent strain of feline calicivirus. Vet Microbiol. 2000;73:281–300. 76. Willi B, Spiri AM, Meli ML, et al. Molecular characterization and virus neutralization patterns of severe, non-epizootic forms of feline calicivirus infections resembling virulent systemic disease in cats in Switzerland and in Liechtenstein. Vet Microbiol. 2016;182:202–12. 77. Pesavento PA, Maclachlan NJ, Dillard-Telm L, et al. Pathologic, immunohistochemical, and electron microscopic findings in naturally occurring virulent systemic feline calicivirus infection in cats. Vet Pathol. 2004;41:257–63. 78. Hurley KE, Pesavento PA, Pedersen NC, et al. An outbreak of virulent systemic feline calicivirus disease. J Am Vet Med Assoc. 2004;224:241–9. 79. Declercq J. Pustular calicivirus dermatitis on the abdomen of two cats following routine ovariectomy. Vet Dermatol. 2005;16:395–400. 80. Smith AW, Iversen PL, O’Hanley PD, et al. Virus-specific antiviral treatment for controlling severe and fatal outbreaks of feline calicivirus infection. Am J Vet Res. 2008;69:23–32. 81. Hartmann K. Clinical aspects of feline retroviruses: a review. Viruses. 2012;4:2684. 82. Favrot C, Wilhelm S, Grest P, et al. Two cases of FeLV-associated dermatoses. Vet Dermatol. 2005;16:407–12. 83. Gross TL, Clark EG, Hargis AM, et al. Giant cell dermatosis in FeLV-positive cats. Vet Dermatol. 1993;4:117–22. 84. Center SA, Scott DW, Scott FW. Multiple cutaneous horns on the footpad of a cat. Feline Practice. 1982;12:26–30. 85. Komori S, Ishida T, Washizu M. Four cases of cutaneous horns in the foot pads of feline leukemia virus-negative cats. J Japan Vet Med Assoc. 1998;51:27–30. 86. Chaher E, Robertson E, Sparkes A, et al. Call for cases: cat paw hyperkeratosis. CVE Control and Therapy Series. 2016;282:51–4. 87. Burr HD, Keating JH, Clifford CA, et al. Cutaneous lymphoma of the tarsus in cats: 23 cases (2000–2012). J Am Vet Med Assoc. 2014;244:1429–34. 88. Fontaine J, Heimann M, Day MJ. Cutaneous epitheliotropic T-cell lymphoma in the cat: a review of the literature and five new cases. Vet Dermatol. 2011;22:454–61. 89. Roccabianca P, Avallone G, Rodriguez A, et al. Cutaneous lymphoma at injection sites: pathological, immunophenotypical, and molecular characterization in 17 cats. Vet Pathol. 2016;53:823–32. 90. Cannon MJ, Silkstone MA, Kipar AM. Cutaneous lesions associated with coronavirus-induced vasculitis in a cat with feline infectious peritonitis and concurrent feline immunodeficiency virus infection. J Feline Med Surg. 2005;7:233–6. 91. Martha JC, Malcolm AS, Anja MK. Cutaneous lesions associated with coronavirus-induced vasculitis in a cat with feline infectious peritonitis and concurrent feline immunodeficiency virus infection. J Feline Med Surg. 2005;7:233–6. 92. Bauer BS, Kerr ME, Sandmeyer LS, et al. Positive immunostaining for feline infectious peritonitis (FIP) in a Sphinx cat with cutaneous lesions and bilateral panuveitis. Vet Ophthalmol. 2013;16(Suppl 1):160–3. 93. Murphy B. Retroviridae. In: NJ ML, Dubovi EJ, editors. Fenner’s Veterinary Virology. 5th ed. London: Academic Press; 2017. p. 269–97. 94. Backel K, Cain C. Skin as a marker of general feline health: cutaneous manifestations of infectious disease. J Feline Med Surg. 2017;19:1149–65. 95. Munday JS, Witham AI. Frequent detection of papillomavirus DNA in clinically normal skin of cats infected and noninfected with feline immunodeficiency virus. Vet Dermatol. 2010;21:307–10. 96. Magden E, Quackenbush SL, VandeWoude S. FIV associated neoplasms—a mini-review. Vet Immunol Immunopathol. 2011;143:227–34. 97. Hutson CA, Rideout BA, Pedersen NC. Neoplasia associated with feline immunodeficiency virus infection in cats of southern California. J Am Vet Med Assoc. 1991;199: 1357–62. VetBooks.ir Leishmaniosis Maria Grazia Pennisi Abstract Leishmania spp. affecting cats include L. infantum, L. mexicana, L. venezuelensis, L. amazonensis, and L. braziliensis. Leishmania infantum is the species most frequently reported in cats and causes feline leishmaniosis (FeL). Cats exposed to L. infantum are able to mount a cell-mediated immune response that does not parallel antibody production. Cats with L. infantum-associated clinical disease have positive blood PCR and low to very high antibody levels. About half of the clinical cases of FeL are diagnosed in cats with impaired immunocompetence. Skin or mucocutaneous lesions are the most common clinical findings; however, FeL is a systemic disease. Skin or mucocutaneous lesions and lymph node enlargement are seen in at least half of cases, ocular or oral lesions and some aspecific signs (weight loss, anorexia, lethargy) in about 20–30% of cases, and many other clinical signs (e.g., respiratory, gastrointestinal) are sporadically observed. Ulcerative and nodular lesions due to diffuse granulomatous dermatitis are the most frequent skin manifestations, mainly distributed on the head or symmetrically on the distal limbs. Diagnosis can be obtained by cytology and histology, and immunohistochemistry is useful to confirm the causative role of Leishmania infection in the dermopathological manifestations; however, other skin diseases may coexist with FeL. Polymerase chain reaction is used in case of suggestive lesions with lack of parasites and for Leishmania speciation. Comorbidities, coinfections, and chronic renal disease influence the prognosis and should be investigated. Treatment is currently based on the same drugs used for canine leishmaniosis, and generally clinical cure is obtained; however recurrence is possible. M. G. Pennisi (*) Dipartimento di Scienze Veterinarie, Università di Messina, Messina, Italy e-mail: mariagrazia.pennisi@unime.it © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_18 387 388 M. G. Pennisi VetBooks.ir Introduction Leishmaniases are protozoan diseases caused by Leishmania spp. affecting humans and animals, but leishmaniosis is the term used for diseases in animals. Leishmaniosis caused by Leishmania infantum is a severe, zoonotic, vector-borne disease endemic in areas of the Old and New Worlds, with dogs as the main reservoir [1]. In fact, the majority of infected dogs do not develop clinical signs or clinicopathological abnormalities, but they are chronically infected and infectious to sand fly vectors. Dogs may, however, develop a mild to severe systemic disease, with frequent skin lesions usually associated with other clinical and clinico-pathological abnormalities. Therefore, much research interest has been focused on canine leishmaniosis (CanL), in order to prevent the infection, understand the pathomechanisms driving infection to disease, make early and accurate diagnosis, and treat affected dogs. Conversely, until about 25 years ago, the cat was considered a resistant host species to Leishmania infections, based on very rare case reports, occasional post mortem finding of the parasite in cats from endemic areas, and results from an experimental infection study demonstrating limited infection rates [2]. Over the last decades, an increasing number of clinical cases have been reported, and investigations with more sensitive diagnostic techniques detected a variable, but not negligible, infection rate in cats living in endemic areas. Therefore, feline leishmaniosis (FeL) appears nowadays as an emergent disease, and the cat’s role as reservoir host is revalued. We now know that the epidemiology of leishmaniosis is complex and the vectorial transmission in endemic areas involves multiple host species infectious to sand flies, including the cat. Tegumentary leishmaniosis caused by dermotropic Leishmania spp. is rarely reported in both dogs and cats. Dermotropic species infecting cats are Leishmania tropica and Leishmania major in the Old World and Leishmania mexicana, Leishmania venezuelensis, and Leishmania braziliensis in the Americas. Main reservoir hosts for dermotropic species are wild animals, such as rodents. Etiology, Diffusion, and Transmission Leishmania genus (Kinetoplastea: Trypanosomatidae) includes diphasic and dixenous protozoans replicating as promastigotes in the gut of phlebotomine sand flies, their natural vectors. When inoculated into vertebrate hosts by sand fly bites, promastigotes change to the non-flagellated amastigote form that multiplies by binary fission in macrophages. Leishmania spp. detected in cats are able to infect also other mammals (including dogs and humans) and belong to the subgenus Leishmania (L. infantum, L. mexicana, L. venezuelensis, L. amazonensis) or Viannia (L. braziliensis). Leishmania infantum is the species most frequently reported in both dogs and cats in the Old World and in Central and South America. Leishmania infantum has been detected in cats in Mediterranean countries (Italy, Spain, Portugal, France, Greece, Turkey, Cyprus), Iran and Brazil [3–6]. Reported antibody and blood PCR prevalences are very variable (from nihil to >60%) and influenced by many factors VetBooks.ir Leishmaniosis 389 such as the local level of endemicity, selection of tested cats and analytical differences [3]. However, L. infantum antibody and molecular prevalence is usually lower in cats compared to dogs and cases of FeL are rarer [3, 7]. Cases of both CanL and FeL are diagnosed in non-endemic areas in dogs or cats rehomed from or travelling to endemic areas [1, 8–13]. Sand fly transmission is the most important way of transmission of Leishmania to humans and animals, and several studies about the feeding habit of sand flies suggest that this is likely also in feline infection, but it has never been investigated [3, 14–16]. Non-vectorial transmission (vertical, by blood transfusion, mating, or bite wounds) of CanL is well known and responsible for autochthonous cases in non-endemic areas in dogs, but we have no evidence of these ways of transmission to and in cats [1, 10, 17, 18]. However, blood transfusion could be a source of infection in cats as proven in dogs and humans. In fact, healthy cats – similarly to healthy dogs and humans – are found blood PCR positive in endemic areas [4–7, 19–22]. Pathogenesis Leishmania infantum A great number of both experimentally and field controlled prospective studies performed on CanL provided information about immunopathogenesis of CanL, but we do not have similar studies performed on cats. In dogs, T helper 1 (Th1) immune response responsible for protective CD4+ T cell-mediated immunity is associated to resistance to the disease [1]. Conversely, progression of L. infantum infection and development of lesions and clinical signs in dogs and humans are associated with a predominant T helper 2 (Th2) immune response and the consequent nonprotective antibody production and T cell exhaustion [23]. Depending on a variable balance between humoral and cell-mediated immunity in the infected dog, a wide and dynamic clinical spectrum is seen in CanL, including subclinical infection, selflimiting mild disease, or severe progressive illness [1, 24]. Sick dogs with severe clinical disease and high blood parasitemia show a high antibody level and lack in specific IFN-γ production [25]. Similarly to what occurs in mouse experimental models, a complex genetic background modulates the dog’s susceptibility or resistance to CanL [1, 24]. In cats, the adaptive immune response elicited by L. infantum exposure in endemic areas was recently explored with measurement of specific antibody and IFN-γ production [26]. Some cats produced L. infantum-specific IFN-γ and were found blood PCR negative and antibody negative or in few cases borderline positive [26]. This means that, similarly to other mammals, cats exposed to L. infantum are able to mount a protective cell-mediated immune response that does not parallel antibody production. The relationship between immunological pattern and severity of disease is still unexplored in cats; however, we know that cats with L. infantum-associated clinical disease have a high blood parasitemia and low to very high antibody levels [3, 27–32]. Moreover, longitudinal studies found that progression of the infection toward disease is associated in cats with increasing antibody titers, and, on the other hand, clinical improvement obtained by anti-L. infantum VetBooks.ir 390 M. G. Pennisi therapy is associated with a significant reduction of antibody levels, similarly to CanL [33–36]. Coinfections with some vector-borne pathogens (e.g., Dirofilaria immitis, Ehrlichia canis, Hepatozoon canis) can influence parasite burden and progression of CanL [37–39]. In cats, the association between retroviral, coronavirus, Toxoplasma, or vector-borne coinfections and antibody and/or PCR positivity to L. infantum has been explored [5, 20, 40–50]. A significant association was found only between feline immunodeficiency virus (FIV) and L. infantum positivity in some cases [41, 46, 48]. Moreover, more than one third of cats with FeL and tested for retroviral coinfections were found positive to FIV [a few were also positive to Feline Leukemia Virus (FeLV)] [11, 12, 27–29, 31, 51–69]. Other FeL cases reported in FIV and FeLV negative cats were diagnosed in animals affected by immune-mediated diseases (and treated with immunosuppressive drugs), neoplasia, or diabetes mellitus, and we may assume that about half of the clinical cases of FeL were diagnosed in cats with impaired immunocompetence [12, 27–30, 34, 52, 59–61]. Despite the fact that skin or mucocutaneous lesions are the most common clinical findings, FeL is considered a systemic disease as CanL. Parasites can be detected in various other tissues, such as lymph nodes, spleen, bone marrow, eye, kidney, liver, and gastrointestinal and respiratory tract [8]. American Dermotropic Leishmania spp. Some scanty information about adaptive immune response of cats toward American dermotropic Leishmania spp. can be inferred only from case reports of L. mexicana and from an experimental infection of cats with L. braziliensis [70–72]. Delayed-type hypersensitivity skin test with L. donovani antigen was repeatedly found negative in a cat affected by recurrent nodular dermatitis caused by L. mexicana infection, suggesting a lack of cell-mediated adaptive immune response in this cat [70]. Anti-Leishmania antibody production seems to be limited, as of five cats with L. mexicana tegumentary leishmaniosis only two were antibody positive at ELISA test, although Western blot test was positive in four [71]. Moreover, in cats intradermally infected with a human strain of L. braziliensis, a short-term antibody production was documented after the development of skin lesions, but, frequently, it appeared after the healing of lesions [72]. Clinical Picture Leishmania infantum Currently, in endemic areas FeL is far less frequently reported than CanL, but we are probably underestimating the disease, particularly the less frequent and less severe clinical presentations, as it occurred in the past with CanL. Furthermore, coinfections or comorbidities are frequently detected which can contribute to a clinical misrepresentation and misdiagnosis of FeL [3, 22, 27–32]. About a hundred of clinical cases were reported over the last 30 years – mostly in Southern Europe – and VetBooks.ir Leishmaniosis 391 they are at present the only source of knowledge about FeL. We are therefore aware of the current low level of evidence (III–IV) for statements and recommendations concerning this disease. Age range of affected cats is wide (2–21 years); however, they are mostly mature cats (median age 7 years) at diagnosis, with very few being 2–3 years old [3, 27, 28, 32, 51, 57, 73]. Both genders are similarly represented and almost all cases are reported in domestic short-hair cats. Some clinical manifestations are very frequent at diagnosis – found in at least half of the cases – such as skin or mucocutaneous lesions and lymph node enlargement. Common presentations – found in one fourth to half of the cats – are represented by ocular or oral lesions and some aspecific signs (weight loss, anorexia, lethargy). Finally, there are many clinical signs seen in less than one fourth of the cases. Usually affected cats display more than one clinical sign and often develop different lesions with time. kin and Mucocutaneous Manifestations S Skin or mucocutaneous manifestations were found in about two thirds of reported cases, but they rarely were the only abnormality detected [3, 8, 27–30, 73]. In a study from a pathology laboratory from Spain, FeL was diagnosed in 0.57% of all skin and ocular biopsies (n = 2632) examined over a 4-year period [73]. Several dermatological entities have been described, and different presentations often coexisted or developed subsequently in the same cat. Most lesions were observed on the head. Pruritus was rarely reported, and in most cats manifesting pruritus, a concurrent dermatological disease was identified such as flea allergy, eosinophilic granuloma, pemphigus foliaceus, squamous cell carcinoma (SCC), or demodicosis [12, 67, 75, 76]. In one case, however, pruritus stopped after starting anti-Leishmania therapy [77]. Ulcerative dermatitis is the more commonly reported skin lesion and sometimes with a history of self-healing and recurrence of lesion. Crusty-ulcerative lesions with raised margins were seen on pressure points (hock, carpal, and ischiatic regions), often symmetrically, and were large up to 5 cm (Fig. 1) [27, 28, 54, 57, 64, Fig. 1 Large ulcer with raised margins on right forelimb. A similar symmetrical lesion was present on the left forelimb VetBooks.ir 392 M. G. Pennisi Fig. 2 Solitary focal ulceration on the face (white arrow) and conjunctival nodule (transparent arrow) observed in the same cat of Fig. 1 Fig. 3 Severe facial ulceration in a cat diagnosed with squamous cell carcinoma associated with L. infantum dermal infection 77]. Focal solitary or multiple smaller ulcers were reported on the face (Fig. 2), lips, ears, neck, or limbs [27, 28, 34, 64, 65, 73, 77–79]. In a few cases focal or diffuse ulcerative dermatitis affected face, trunk, or footpads [27, 63, 65, 79]. Ulceration of the nasal planum was also reported, and in one case it was associated with concurrent SCC [30, 54, 58, 67]. Leishmania infection and SCC were found associated in biopsied tissues obtained from a deep facial ulceration (Fig. 3) in other two cases [56, 76]. Unfortunately, the diagnosis of SCC was missed at first consultation in two cases when only Leishmania infection was detected by cytology or histology [30, 76]. Moreover, multifocal ulcerative dermatitis caused by L. infantum was diagnosed in a cat suffering from SCC at a different site [65]. Ulcerative dermatitis was found associated with eosinophilic granuloma complex, and in one other case Leishmania infection was confirmed (by serology and skin PCR) in a cat with pemphigus foliaceus [12, 73]. VetBooks.ir Leishmaniosis 393 Nodular dermatitis is also a frequent dermatological manifestation, and single, multiple or diffuse, firm, alopecic, non-painful nodules were detected. They are usually small (<1 cm), mainly distributed on the head and, in descending order of frequency, on the eyelid, ear, chin, nose, lips, and tongue [11, 27, 28, 31, 55, 64, 66, 73, 80–83]. Nodules can be found also on limbs or rarely on the trunk or the anus [12, 55, 73]. In rare cases nodules were ulcerated [12, 66, 84]. Differently from CanL, facial or diffuse scaling and alopecia are less frequently reported in FeL, and in few of these cases, histopathological evaluation confirmed the presence of amastigotes in the affected skin [29, 63, 73]. Digital hyperkeratosis was found in one case only [27]. An atypical FeL presentation that is not reported in CanL is development of hemorrhagic bullae, observed in three cases, respectively, on the nasal planum, head, and margin of the pinna [34, 76]. However, the lesion developed on the nasal planum was histologically diagnosed as hemangioma [76]. The other two cases were cytologically evaluated and amastigotes were found [34]. Visceral Manifestations Lymph node enlargement is the most frequent non-dermatological finding [3]. It is usually multicentric and can be symmetrical. Lymph nodes are firm and non-painful, and enlargement can be relevant mimicking neoplasia. Monolateral or bilateral ocular lesions were reported in about one third of cases, but a specialistic ophthalmic examination was not performed in all cats with FeL; therefore, some less severe ocular findings could have been missed. Conjunctivitis (including also conjunctival nodules) and uveitis are the most frequent ocular manifestations [11, 27, 31, 34, 60, 62, 64, 68, 73]. Keratitis, keratouveitis, and chorioretinitis were diagnosed in a few cats [27, 31, 34, 67, 78]. Panophthalmitis is the consequence of progressive extension of diffuse granulomatous inflammation in case of late diagnosis [60, 73]. Apart from single cases of gingival ulceration, nodular glossitis, or epulid-like lesions, chronic stomatitis and faucitis was found in about 20% of cats, and the parasite was detected in the inflamed oral tissue [27, 31–34, 52, 58, 60, 62, 66, 78, 83]. Non-specific manifestations as weight loss, anorexia, or lethargy were not very frequent [3], and occasionally gastrointestinal (vomiting, diarrhea) or respiratory (chronic nasal discharge, stertor, dyspnea, wheezing) signs were reported [3, 74]. Rare manifestations were icterus, fever, spleen or liver enlargement, and abortion [3]. Interestingly, chronic leishmanial rhinitis was confirmed in some cases [58, 64, 73–75]. American Tegumentary Leishmaniosis (ATL) A limited number of cases of feline cutaneous leishmaniosis caused by dermotropic Leishmania species were reported in the Americas [70, 71, 85–91]. Not always Leishmania speciation was obtained from affected cats, and L. mexicana could be identified in nine cases [70, 71, 91], L. braziliensis in five [85–88], L. venezuelensis in four [90], and L. amazonensis in one [89]. They were all domestic short-hair VetBooks.ir 394 M. G. Pennisi cats and younger (age range: 8 months–11 years; median age 4 years) than cats with disease caused by L. infantum. The most common manifestation consisted in solitary or multiple firm nodules as large as 3 × 2 cm. They were alopecic, variably erythematous, or ulcerated and mainly distributed on the pinnae and the face (eyelids, nasal planum, muzzle) and rarely on the distal limbs or tail. A larger (6 cm) interdigital ovoid lesion was reported in a cat with L. braziliensis infection [88]. Nasal or ear ulcerations were seen in two cats with L. mexicana infection and in two others (nasal planum or medial canthus) with L. braziliensis infection [71, 86, 87]. Mucosal nodules may develop in the nasal cavity causing sneezing, stertor, and inspiratory dyspnea [71, 85]. No other manifestations were reported in cats with ATL; however, some followed up cases of L. venezuelensis or L. mexicana infections developed new nodular lesions at other sites [70, 90]. Diagnosis Diagnostic testing of symptomatic cats aims to confirm Leishmania infection and to establish a causal relationship with the clinical picture. In case of dermatological or mucosal lesions, the cytological evaluation of impression smears from erosions and ulcers, of scrapings from margins of deep ulcers, and of fine needle punction of nodules can show a pyogranulomatous pattern and the presence of amastigotes (in the cytoplasm of macrophages or extracellularly) (Fig. 4) [3, 71]. Amastigotes have an elliptic shape with pointed ends, measure about 3–4 × 2 μm, and are characterized by the rod-shaped basophilic kinetoplast set perpendicular to the large nucleus. Morphology of amastigotes does not allow to differentiate between Leishmania species. In cats with leishmaniosis caused by L. infantum, amastigotes can be found also in cytological samples from enlarged lymph nodes, bone marrow, nasal exudates, liver, and spleen and rarely in circulating neutrophils [3]. Fig. 4 Cytology from the cutaneous lesion in Fig. 1. Macrophagic–neutrophilic inflammation with numerous intracellular (arrows) and extracellular amastigotes. In some extracellular amastigotes the basophilic rod-shaped kinetoplast is clearly visible (arrow heads) (May Grünwald–Giemsa stain 1000×) VetBooks.ir Leishmaniosis 395 Biopsy of skin or mucosal lesions is required when cytology is inconclusive and in any case when the clinical presentation is compatible with neoplastic or immune-mediated diseases. Amastigotes are not easily detected by the conventional histological staining, and in suspected cases they should be investigated by immunohistochemistry (Fig. 5). However, immunohistochemistry does not allow the speciation of Leishmania amastigotes, which can be obtained by polymerase chain reaction (PCR) and sequencing of amplicons. PCR can be performed also from cytological slides, formalin-fixed and paraffin-embedded biopsies. Quantitative real-time PCR is very sensitive and can provide parasite load of samples. Dermopathological evaluation (Fig. 6) shows dermal periadnexal to diffuse granulomatous inflammation with a diffuse infiltration of macrophages, a moderate number of amastigotes, and a variable number of lymphocytes and plasma cells [12, 73]. The overlying epidermis is affected by hyperkeratosis, acanthosis, and ulceration [73]. In nodular lesions giants cells may be seen [73]. A low number of parasites were found in nodular lesions, characterized by perifollicular granulomatous Fig. 5 Dark brown amastigotes evidenced by immunohistochemistry. Mayer’s hematoxylin counterstain. Bar = 10 μm. (Courtesy of R. Puleio, IZS Sicilia, Italy) Fig. 6 Diffuse pyogranulomatous dermatitis (a) with numerous amastigotes within macrophages (b). HE. Bar = 10 μm. (Courtesy of R. Puleio, IZS Sicilia, Italy) VetBooks.ir 396 M. G. Pennisi dermatitis and in a lichenoid interface dermatitis in a cat affected by scaly dermatitis [73]. Mucosal (and mucocutaneous) lesions harbor a higher parasite load and submucosal diffuse granulomatous inflammation is seen [62, 68, 73]. In some cases, a dermal, diffuse, granulomatous inflammation was found associated with lesions characteristic of feline eosinophilic granuloma complex [54, 73]. A transepidermal inflammatory infiltrate with parasitized macrophages was reported in the neoplastic tissue of a cat diagnosed with concurrent SCC [56]. In another case, a stromal infiltration of parasitized macrophages was observed adjacent to islands of SCC [30]. Nodular to diffuse granulomatous dermatitis with hyperkeratotic, hyperplastic, and often ulcerated epidermis is described in cases of ATL [71, 85, 91]. Anti-L. infantum antibody detection is performed by quantitative serology (IFAT, ELISA, or DAT) and Western blot (WB) techniques [3]. Cutoff setting for IFAT is established at 1:80 dilution, and almost all cats affected by clinical FeL caused by L. infantum have low to very high antibody levels [43, 92]. Conversely, sick cats with ATL may not have detectable circulating antibodies [71]. Culture of infected tissues provided feline strains that in most cases showed the same zymodemes and genotypes detected in dogs or humans [3, 30]. Clinico-pathological abnormalities more frequently reported at diagnosis in cats with FeL caused by L. infantum consisted in mild to moderate non-regenerative anemia, hyperglobulinemia, and proteinuria [3]. Chronic kidney disease (CKD), in most cases at an early stage (International Renal Interest Society [IRIS] stages 1 or 2), is often documented when a renal profile including urinalysis and the urine to protein concentrations ratio is performed [32, 75]. Clinico-pathological abnormalities of cats with ATL were rarely investigated and only eosinophilia and neutrophilia were found in one cat with L. braziliensis infection [70, 85]. Treatment and Prognosis Treatment of cats with clinical FeL caused by L. infantum is empirical and based on off-label use of the most common drugs prescribed to dogs with CanL [3]. Longterm oral administration of allopurinol (10–20 mg/kg once or twice daily) as monotherapy or as maintenance treatment after a course of subcutaneous injections of meglumine antimoniate (50 mg/kg once daily for 30 days) are the most frequently used regimens. Clinical cure is usually obtained, but efficacy and safety of used protocols have never been evaluated in controlled studies; therefore cats should be monitored very carefully for adverse effects during treatment (particularly cats affected by renal disease) and for possible clinical recurrence after stopping the therapy [3, 27–32, 34, 74]. A cutaneous adverse drug reaction (head and neck erythema, alopecia, exfoliation, and crusting) was suspected few days after starting allopurinol in a cat [75]. The skin reaction rapidly solved after stopping allopurinol [75]. Increases in liver enzymes were observed in another cat, and they resolved VetBooks.ir Leishmaniosis 397 after lowering dosage to 5 mg/kg twice a day [12]. In two further cases, acute kidney injury was diagnosed few weeks after starting allopurinol administration [32]. In another cat with concurrent IRIS stage 1-CKD at the time of FeL diagnosis, azotemia developed after meglumine antimoniate and afterward to miltefosine (2 mg/ kg orally once daily for 30 days) administration. [75] This latter cat was hereafter maintained with a dietary supplementation of nucleotides and active hexose correlated compounds that was recently found effective in dogs as CanL maintenance treatment [75, 93]. Domperidone (0.5 mg/kg orally once daily) was recently used in two cats in association with allopurinol, and miltefosine was given in one other case [27, 29, 30]. Surgical removal of nodules was performed but generally they recurred [12, 27, 54, 81]. In one case an integrated approach between surgery and chemotherapy was needed for treating large ulcerations [28]. Clinical recurrence is associated with raised antibody titer and parasite load [34]. Cats with clinical FeL may live for several years after diagnosis, even those untreated and/or FIV positive, unless concurrent conditions (neoplasia) and complications (chronic kidney disease) occur or develop [32, 68]. Scant information is available about treatment and prognosis of ATL. Some cats with L. mexicana ATL were cured after surgical excision of nodules [91]. However, radical pinnectomy was not effective in a FIV- and FeLV-negative cat and lesions recurred at pinnectomy site in about 2 years [70]. Subsequently new lesions progressively involved the muzzle and finally the nasal mucosa, and the cat was euthanized over 6 years after ATL diagnosis due to a mediastinal lymphosarcoma [70]. Prevention of L. infantum Infection Individual protection of exposed cats reduces their risk to be infected by sand fly bites and to develop the clinical disease [3, 22]. Phlebotomus perniciosus and Lutzomyia longipalpis, proven vectors of L. infantum, respectively, in the Old and New Worlds, were found infected after feeding on one single sick cat with FeL [33, 94]. This means that protection of cats at population level contributes to the regional control of L. infantum infection. In fact, the percentage of antibody and/or PCRpositive cats is often not negligible in endemic areas [3–6, 20, 21, 41, 42, 45, 47]. Pyrethroids are used in dogs for preventing the bites of sand flies, but most of them are toxic to cats [3, 95]. Collars containing a combination of 10% imidacloprid and 4.5% flumethrin are the only pyrethroid formulation licensed also for cats, and it was effective in reducing incidence of L. infantum infection in cats living in endemic areas [22]. According to current knowledge, testing of blood donors by antibody detection and blood PCR is the only advisable measure for preventing non-vectorial transmission in cats [96]. 398 M. G. 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González E, Jiménez M, Hernández S, Martín-Martín I, Molina R. Phlebotomine sand fly survey in the focus of leishmaniasis in Madrid, Spain (2012–2014): seasonal dynamics, Leishmania infantum infection rates and blood meal preferences. Parasit Vectors. 2017;10:368. 15. Afonso MM, Duarte R, Miranda JC, Caranha L, Rangel EF. Studies on the feeding habits of Lutzomyia (Lutzomyia) longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) populations from endemic areas of American visceral leishmaniasis in Northeastern Brazil. J Trop Med. 2012;2012:1. https://doi.org/10.1155/2012/858657. 16. Baum M, Ribeiro MC, Lorosa ES, Damasio GA, Castro EA. Eclectic feeding behavior of Lutzomyia (Nyssomyia) intermedia (Diptera, Psychodidae, Phlebotominae) in the transmission area of American cutaneous leishmaniasis, State of Paranà. Brazil Rev Soc Bras Med Trop. 2013;46:547–54. 17. Karkamo V, Kaistinen A, Näreaho A, Dillard K, Vainio-Siukola K, Vidgrén G, Tuoresmäki N, Anttila M. The first report of autochthonous non-vector-borne transmission of canine leishmaniosis in the Nordic countries. Acta Vet Scand. 2014;56:84. 18. Naucke TJ, Amelung S, Lorentz S. First report of transmission of canine leishmaniosis through bite wounds from a naturally infected dog in Germany. Parasit Vectors. 2016;9:256. VetBooks.ir Leishmaniosis 399 19. Pennisi MG, Hartmann K, Addie DD, Lutz H, Gruffydd-Jones T, Boucraut-Baralon C, Egberink H, Frymus T, Horzinek MC, Hosie MJ, Lloret A, Marsilio F, Radford AD, Thiry E, Truyen U, Möstl K. European Advisory Board on Cat Diseases. Blood transfusion in cats: ABCD guidelines for minimising risks of infectious iatrogenic complications. J Feline Med Surg. 2015;17:588–93. 20. Persichetti M-F, Solano-Gallego L, Serrano L, Altet L, Reale S, Masucci M, Pennisi M-G. Detection of vector-borne pathogens in cats and their ectoparasites in southern Italy. Parasit Vectors. 2016;9:247. 21. Akhtardanesh B, Sharifi I, Mohammadi A, Mostafavi M, Hakimmipour M, Pourafshar NG. Feline visceral leishmaniasis in Kerman, southeast of Iran: Serological and molecular study. J Vector Borne Dis. 2017;54:96–102. 22. Brianti E, Falsone L, Napoli E, Gaglio G, Giannetto S, Pennisi MG, Priolo V, Latrofa MS, Tarallo VD, Solari Basano F, Nazzari R, Deuster K, Pollmeier M, Gulotta L, Colella V, DantasTorres F, Capelli G, Otranto D. Prevention of feline leishmaniosis with an imidacloprid 10%/ flumethrin 4.5% polymer matrix collar. Parasit Vectors. 2017;10:334. 23. Esch KJ, Juelsgaard R, Martinez PA, Jones DE, Petersen CA. Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. J Immunol. 2013;191:5542–50. 24. de Vasconcelos TCB, Furtado MC, Belo VS, Morgado FN, Figueiredo FB. Canine susceptibility to visceral leishmaniasis: A systematic review upon genetic aspects, considering breed factors and immunological concepts. Infect Genet Evol. 2019;74:103293. https://doi. org/10.1016/j.meegid.2017.10.005. 25. Solano-Gallego L, Montserrrat-Sangrà S, Ordeix L, Martínez-Orellana P. Leishmania infantum-specific production of IFN-γ and IL-10 in stimulated blood from dogs with clinical leishmaniosis. Parasit Vectors. 2016;9:317. 26. Priolo, V, Martínez Orellana, P, Pennisi, MG, Masucci, M, Foti, M, Solano-Gallego, L. Leishmania infantum specific production of IFNγ in stimulated blood from outdoor cats in endemic areas. In: Proceedings World Leish 6, Toledo-Spain (16th–20th May 2017), 2017: C1038. 27. Bardagi, M, Lloret, A, Dalmau, A, Esteban, D, Font, A, Leiva, M, Ortunez, A, Pena, T, Real, L, Salò, F, Tabar, MD. Feline Leishmaniosis: 15 cases. In: Proceedings 8th World Congress of Veterinary Dermatology, Toledo-Spain (31st May–4th June 2016), 2016: 112–113. 28. Basso MA, Marques C, Santos M, Duarte A, Pissarra H, Carreira LM, Gomes L, Valério-Bolas A, Tavares L, Santos-Gomes G, Pereira da Fonseca I. Successful treatment of feline leishmaniosis using a combination of allopurinol and N-methyl-glucamine antimoniate. JFMS Open Rep. 2016;2:205511691663000. https://doi.org/10.1177/2055116916630002. 29. Dedola, C, Ibba, F, Manca, T, Garia, C, Abramo, F. Dermatite esfoliativa associata a leishmaniosi in un gatto. Paper presented at 2° Congresso Nazionale SIDEV, Aci Castello-Catania, Italy, 17th–19th July 2015. 30. Maia C, Sousa C, Ramos C, Cristóvão JM, Faísca P, Campino L. First case of feline leishmaniosis caused by Leishmania infantum genotype E in a cat with a concurrent nasal squamous cell carcinoma. JFMS Open Rep. 2015;1:205511691559396. https://doi. org/10.1177/2055116915593969. 31. Pimenta P, Alves-Pimenta S, Barros J, Barbosa P, Rodrigues A, Pereira MJ, Maltez L, Gama A, Cristóvão JM, Campino L, Maia C, Cardoso L. Feline leishmaniosis in Portugal: 3 cases (year 2014). Vet Parasitol Reg Stud Reports. 2015;1–2:65–9. https://doi.org/10.1016/j. vprsr.2016.02.003. 32. Pennisi MG, Persichetti MF, Migliazzo A, De Majo M, Iannelli NM, Vitale F. Feline leishmaniosis: clinical signs and course in 14 followed up cases. Atti LXX Convegno SISVET. 2016;70:166–7. 33. Maroli M, Pennisi MG, Di Muccio T, Khoury C, Gradoni L, Gramiccia M. Infection of sandflies by a cat naturally infected with Leishmania infantum. Vet Parasitol. 2007;145:357–60. 34. Pennisi MG, Venza M, Reale S, Vitale F, Lo Giudice S. Case report of leishmaniasis in four cats. Vet Res Commun. 2004;28(Suppl 1):363–6. VetBooks.ir 400 M. G. Pennisi 35. Foglia Manzillo V, Di Muccio T, Cappiello S, Scalone A, Paparcone R, Fiorentino E, Gizzarelli M, Gramiccia M, Gradoni L, Oliva G. Prospective study on the incidence and progression of clinical signs in naïve dogs naturally infected by Leishmania infantum. PLoS Negl Trop Dis. 2013;7:e2225. 36. Solano-Gallego L, Di Filippo L, Ordeix L, Planellas M, Roura X, Altet L, MartínezOrellana P, Montserrat S. Early reduction of Leishmania infantum-specific antibodies and blood parasitemia during treatment in dogs with moderate or severe disease. Parasit Vectors. 2016;9:235. 37. De Tommasi AS, Otranto D, Dantas-Torres F, Capelli G, Breitschwerdt EB, de Caprariis D. Are vector-borne pathogen co-infections complicating the clinical presentation in dogs? Parasit Vectors. 2013;6:97. 38. Morgado FN, Cavalcanti ADS, de Miranda LH, O’Dwyer LH, Silva MRL, da, Menezes, R.C, Andrade da Silva AV, Boité MC, Cupolillo E, Porrozzi R. Hepatozoon canis and Leishmania spp. coinfection in dogs diagnosed with visceral leishmaniasis. Braz J Vet Parasitol. 2016;25:450–8. 39. Tabar MD, Altet L, Martínez V, Roura X. Wolbachia, filariae and Leishmania coinfection in dogs from a Mediterranean area. J Small Anim Pract. 2013;54:174–8. 40. Ayllón T, Diniz PPVP, Breitschwerdt EB, Villaescusa A, Rodríguez-Franco F, Sainz A. Vectorborne diseases in client-owned and stray cats from Madrid. Spain Vector Borne Zoonotic Dis. 2012;12:143–50. 41. Pennisi MG, Masucci M, Catarsini O. Presenza di anticorpi anti-Leishmania in gatti FIV+ che vivono in zona endemica. Atti LII Convegno SISVET. 1998;52:265–6. 42. Pennisi MG, Maxia L, Vitale F, Masucci M, Borruto G, Caracappa S. Studio sull’infezione da Leishmania mediante PCR in gatti che vivono in zona endemica. Atti LIV Convegno SISVET. 2000;54:215–6. 43. Pennisi MG, Lupo T, Malara D, Masucci M, Migliazzo A, Lombardo G. Serological and molecular prevalence of Leishmania infantum infection in cats from Southern Italy. J Feline Med Surg. 2012;14:656–7. 44. Persichetti MF, Pennisi MG, Vullo A, Masucci M, Migliazzo A, Solano-Gallego L. Clinical evaluation of outdoor cats exposed to ectoparasites and associated risk for vector-borne infections in southern Italy. Parasit Vectors. 2018;11:136. 45. Sherry K, Miró G, Trotta M, Miranda C, Montoya A, Espinosa C, Ribas F, Furlanello T, Solano-Gallego L. A serological and molecular study of Leishmania infantum infection in cats from the Island of Ibiza (Spain). Vector Borne Zoonotic Dis. 2011;11:239–45. 46. Sobrinho LSV, Rossi CN, Vides JP, Braga ET, Gomes AAD, de Lima VMF, Perri SHV, Generoso D, Langoni H, Leutenegger C, Biondo AW, Laurenti MD, Marcondes M. Coinfection of Leishmania chagasi with Toxoplasma gondii, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) in cats from an endemic area of zoonotic visceral leishmaniasis. Vet Parasitol. 2012;187:302–6. 47. Solano-Gallego L, Rodríguez-Cortés A, Iniesta L, Quintana J, Pastor J, Espada Y, Portús M, Alberola J. Cross-sectional serosurvey of feline leishmaniasis in ecoregions around the Northwestern Mediterranean. Am J Trop Med Hyg. 2007;76:676–80. 48. Spada E, Proverbio D, Migliazzo A, Della Pepa A, Perego R, Bagnagatti De Giorgi G. Serological and molecular evaluation of Leishmania infantum infection in stray cats in a nonendemic area in Northern Italy. ISRN Parasitol. 2013;2013:1. https://doi.org/10.5402/2013/916376. 49. Spada E, Canzi I, Baggiani L, Perego R, Vitale F, Migliazzo A, Proverbio D. Prevalence of Leishmania infantum and co-infections in stray cats in northern Italy. Comp Immunol Microbiol Infect Dis. 2016;45:53–8. 50. Vita S, Santori D, Aguzzi I, Petrotta E, Luciani A. Feline leishmaniasis and ehrlichiosis: serological investigation in Abruzzo region. Vet Res Commun. 2005;29(Suppl 2):319–21. 51. Britti D, Vita S, Aste A, Williams DA, Boari A. Sindrome da malassorbimento in un gatto con leishmaniosi. Atti LIX Convegno SISVET. 2005;59:281–2. 52. Caracappa S, Migliazzo A, Lupo T, Lo Dico M, Calderone S, Reale S, Currò V, Vitale M. Analisi biomolecolari, sierologiche ed isolamento in un gatto infetto da Leishmania spp. Atti. X Congresso Nazionale SIDiLV. 2008;10:134–5. VetBooks.ir Leishmaniosis 401 53. Coelho WMD, de Lima VMF, Amarante AFT, do, Langoni, H, Pereira VBR, Abdelnour A, Bresciani KDS. Occurrence of Leishmania (Leishmania) chagasi in a domestic cat (Felis catus) in Andradina, São Paulo, Brazil: case report. Rev Bras Parasitol Vet. 2010;19:256–8. 54. Dalmau A, Ossó M, Oliva A, Anglada L, Sarobé X, Vives E. Leishmaniosis felina a propósito de un caso clínico. Clínica Vet Pequeños Anim. 2008;28:233–8. 55. Fileccia, I. Qual’è la vostra diagnosi? Paper presented at 1st Congresso Nazionale SIDEV, Montesilvano (Pescara, Italia), 21–23, September 2012. 56. Grevot A, Jaussaud Hugues P, Marty P, Pratlong F, Ozon C, Haas P, Breton C, Bourdoiseau G. Leishmaniosis due to Leishmania infantum in a FIV and FELV positive cat with a squamous cell carcinoma diagnosed with histological, serological and isoenzymatic methods. Parasite Paris. 2005;12:271–5. 57. Hervás J, Chacón-M De Lara F, Sánchez-Isarria MA, Pellicer S, Carrasco L, Castillo JA, Gómez-Villamandos JC. Two cases of feline visceral and cutaneous leishmaniosis in Spain. J Feline Med Surg. 1999;1:101–5. 58. Ibba, F. Un caso di rinite cronica in corso di leishmaniosi felina. In: Proceedings 62nd Congresso Internazionale Multisala SCIVAC, Rimini-Italy (29th–31st May 2009), 2009:568. 59. Laruelle-Magalon C, Toga I. Un cas de leishmaniose féline. Prat Méd Chir Anim Comp. 1996;31:255–61. 60. Leiva M, Lloret A, Peña T, Roura X. Therapy of ocular and visceral leishmaniasis in a cat. Vet Ophthalmol. 2005;8:71–5. 61. Marcos R, Santos M, Malhão F, Pereira R, Fernandes AC, Montenegro L, Roccabianca P. Pancytopenia in a cat with visceral leishmaniasis. Vet Clin Pathol. 2009;38:201–5. 62. Migliazzo A, Vitale F, Calderone S, Puleio R, Binanti D, Abramo F. Feline leishmaniosis: a case with a high parasitic burden. Vet Dermatol. 2015;26:69–70. 63. Ozon C, Marty P, Pratlong F, Breton C, Blein M, Lelièvre A, Haas P. Disseminated feline leishmaniosis due to Leishmania infantum in Southern France. Vet Parasitol. 1998;75:273–7. 64. Pennisi, MG, Lupo, T, Migliazzo, A, Persichetti, M-F, Masucci, M, Vitale, F. Feline Leishmaniosis in Italy: Restrospective evaluation of 24 clinical cases. In: Proceedings World Leish 5, Porto de Galinhas, Pernambuco-Brazil (13th–17th May 2013), 2013:P837. 65. Pocholle E, Reyes-Gomez E, Giacomo A, Delaunay P, Hasseine L, Marty P. A case of feline leishmaniasis in the south of France. Parasite Paris Fr. 2012;19:77–80. 66. Poli A, Abramo F, Barsotti P, Leva S, Gramiccia M, Ludovisi A, Mancianti F. Feline leishmaniosis due to Leishmania infantum in Italy. Vet Parasitol. 2002;106:181–91. 67. Sanches A, Pereira AG, Carvalho JP. Um caso de leishmaniose felina. Vet Med. 2011;63:29–30. 68. Verneuil M. Ocular leishmaniasis in a cat: case report. J Fr Ophtalmol. 2013;36:e67–72. 69. Vides JP, Schwardt TF, Sobrinho LSV, Marinho M, Laurenti MD, Biondo AW, Leutenegger C, Marcondes M. Leishmania chagasi infection in cats with dermatologic lesions from an endemic area of visceral leishmaniosis in Brazil. Vet Parasitol. 2011;78:22–8. 70. Barnes JC, Stanley O, Craig TM. Diffuse cutaneous leishmaniasis in a cat. J Am Vet Med Assoc. 1993;202:416–8. 71. Rivas AK, Alcover M, Martínez-Orellana P, Montserrat-Sangrà S, Nachum-Biala Y, Bardagí M, Fisa R, Riera C, Baneth G, Solano-Gallego L. Clinical and diagnostic aspects of feline cutaneuous leishmaniosis in Venezuela. Parasit Vectors. 2018;11:141. 72. Simões-Mattos L, Mattos MRF, Teixeira MJ, Oliveira-Lima JW, Bevilacqua CML, Prata-Júnior RC, Holanda CM, Rondon FCM, Bastos KMS, Coêlho ICB, Barral A, Pompeu MML. The susceptibility of domestic cats (Felis catus) to experimental infection with Leishmania braziliensis. Vet Parasitol. 2005;127:199–208. 73. Navarro JA, Sánchez J, Peñafiel-Verdú C, Buendía AJ, Altimira J, Vilafranca M. Histopathological lesions in 15 cats with leishmaniosis. J Comp Pathol. 2010;143:297–302. 74. Altuzarra R, Movilla R, Roura X, Espada Y, Majo N, Novella R. Computed tomography features of destructive granulomatous rhinitis with intracranial extension secondary to leishmaniasis in a cat. Vet Radiol Ultrasound. 2018; https://doi.org/10.1111/vru.12666. 75. Leal RO, Pereira H, Cartaxeiro C, Delgado E, Peleteiro MDC. Pereira da Fonseca, I. Granulomatous rhinitis secondary to feline leishmaniosis: report of an unusual presentation and therapeutic complications. JFMS Open Rep. 2018;4(2):2055116918811374. VetBooks.ir 402 M. G. Pennisi 76. Laurelle-Magalon C, Toga I. Un cas de leishmaniose féline. Prat Med Chir Anim Comp. 1996;31:255–61. 77. Monteverde, V, Polizzi, D, Lupo, T, Fratello, A, Leone, C, Buffa, F, Vazzana, I, Pennisi, MG. Descrizione di un carcinoma a cellule squamose in corso di leishmaniosi in un gatto. Atti Congresso Nazionale ceedings of the 7th National Congress of the Italian Society of Veterinary Laboratory Diagnostics (SiDiLV). Perugia 9–10 November. 2006;7:329–330. 78. Ennas F, Calderone S, Caprì A, Pennisi MG. Un caso di leishmaniosi felina in Sardegna. Veterinaria. 2012;26:55–9. 79. Hervás J, Chacón-Manrique de Lara F, López J, Gómez-Villamandos JC, Guerrero MJ, Moreno A. Granulomatous (pseudotumoral) iridociclitis associated with leishmaniasis in a cat. Vet Rec. 2001;149:624–5. 80. Cohelo WM, Lima VM, Amarante AF, Langoni H, Pereira VB, Abdelnour A, Bresciani KD. Occurrence of Leishmania (Leishmania) chagasi in a domestic act (Felis catus) in Andradina, São Paulo, Brazil: case report. Rev Bras Parasitol Vet. 2010;19:256–8. 81. Costa-Durão JF, Rebelo E, Peleteiro MC, Correira JJ, Simões G. Primeiro caso de leishmaniose em gato doméstico (Felis catus domesticus) detectado em Portugal (Concelho de Sesimbra). Nota preliminar Rev Port Cienc Vet. 1994;89:140–4. 82. Savani ES, de Oliveira Camargo MC, de Carvalho MR, Zampieri RA, dos Santos MG, D’Auria SR, Shaw JJ, Floeter-Winter LM. The first record in the Americas of an autochtonous case of Leishmania (Leishmania) infantum chagasi in a domestic cat (Felix catus) from Cotia County, São Paulo State. Brazil Vet Parasitol. 2004;120:229–33. 83. Ortuñez, A, Gomez, P, Verde, MT, Mayans, L, Villa, D, Navarro, L. Lesiones granulomatosas en la mucosa oral y lengua y multiples nodulos cutaneos en un gato causado por Leishmania infantum. In: Proceedings Southern European Veterinary Conference (SEVC), BarcelonaSpain (30th September–3rd October 2011). 84. Attipa C, Neofytou K, Yiapanis C, Martínez-Orellana P, Baneth G, Nachum-Biala Y, BrooksBrownlie H, Solano-Gallego L, Tasker S. Follow-up monitoring in a cat with leishmaniosis and coinfections with Hepatozoon felis and “Candidatus Mycoplasma haemominutum”. JFMS Open Rep. 2017;3:205511691774045. https://doi.org/10.1177/2055116917740454. 85. Schubach TM, Figuereido FB, Pereira SA, Madeira MF, Santos IB, Andrade MV, Cuzzi T, Marzochi MC, Schubach A. American cutaneous leishmaniasis in two cats from Rio de Janeiro, Brazil: first report of natural infection with Leishmania (Viannia) braziliensis. Trans R Soc Trop Med Hyg. 2004;98:165–7. 86. Ruiz RM, Ramírez NN, Alegre AE, Bastiani CE, De Biasio MB. Detección de Leishmania (Viannia) braziliensis en gato doméstico de Corrientes, Argentina, por técnicas de biología molecular. Rev Vet. 2015;26:147–50. 87. Rougeron V, Catzeflis F, Hide M, De Meeûs T, Bañuls A-L. First clinical case of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis in a domestic cat from French Guiana. Vet Parasitol. 2011;181:325–8. 88. Passos VM, Lasmar EB, Gontijo CM, Fernandes O, Degrave W. Natural infection of a domestic cat (Felis domesticus) with Leishmania (Viannia) in the metropolitan region of Belo Horizonte, State of Minas Gerais. Brazil Mem Inst Oswaldo Cruz. 1996;91:19–20. 89. de Souza AI, Barros EM, Ishikawa E, Ilha IM, Marin GR, Nunes VL. Feline leishmaniasis due to Leishmania (Leishmania) amazonensis in Mato Grosso do Sul State. Brazil Vet Parasitol. 2005;128:41–5. 90. Bonfante-Garrido R, Valdivia O, Torrealba J, García MT, Garófalo MM, Urdaneta R, Alvarado J, Copulillo E, Momen H, Grimaldi G Jr. Cutaneous leishmaniasis in cats (Felis domesticus) caused by Leishmania (Leishmania) venezuelensis. Revista Científica, FCV-LUZ. 1996;6:187–90. 91. Trainor KE, Porter BF, Logan KS, Hoffman RJ, Snowden KF. Eight cases of feline cutaneous leishmaniasis in Texas. Vet Pathol. 2010;47:1076–81. VetBooks.ir Leishmaniosis 403 92. Persichetti MF, Solano-Gallego L, Vullo A, Masucci M, Marty P, Delaunay P, Vitale F, Pennisi MG. Diagnostic performance of ELISA, IFAT and Western blot for the detection of anti-Leishmania infantum antibodies in cats using a Bayesian analysis without a gold standard. Parasit Vectors. 2017;10:119. 93. Segarra S, Miró G, Montoya A, Pardo-Marín L, Boqué N, Ferrer L, Cerón J. Randomized, allopurinol-controlled trial of the effects of dietary nucleotides and active hexose correlated compound in the treatment of canine leishmaniosis. Vet Parasitol. 2017;239:50–6. 94. da Silva SM, Rabelo PFB, Gontijo, N. de F, Ribeiro RR, Melo MN, Ribeiro VM, Michalick MSM. First report of infection of Lutzomyia longipalpis by Leishmania (Leishmania) infantum from a naturally infected cat of Brazil. Vet Parasitol. 2010;174:150–4. 95. Brianti E, Gaglio G, Napoli E, Falsone L, Prudente C, Solari Basano F, Latrofa MS, Tarallo VD, Dantas-Torres F, Capelli G, Stanneck D, Giannetto S, Otranto D. Efficacy of a slow- release imidacloprid (10%)/flumethrin (4.5%) collar for the prevention of canine leishmaniosis. Parasit Vectors. 2014;7:327. 96. Pennisi MG, Hartmann K, Addie DD, Lutz H, Gruffydd-Jones T, Boucraut-Baralon C, Egberink H, Frymus T, Horzinek MC, Hosie MJ, Lloret A, Marsilio F, Radford AD, Thiry E, Truyen U, Möstl K. European Advisory Board on Cat Diseases. Blood transfusion in cats: ABCD guidelines for minimising risks of infectious iatrogenic complications. J Feline Med Surg. 2015;17:588–93. VetBooks.ir Ectoparasitic Diseases Federico Leone and Hock Siew Han Abstract Ectoparasitic skin diseases are extremely common in cats, and their correct identification is very important for both the cat’s and the owner’s welfare. In this chapter, the most important feline ectoparasitic diseases will be discussed, including the morphological features of the parasite, clinical signs, diagnostic techniques and therapeutic options. The majority of these diseases can be diagnosed with tests that can be easily performed during the clinical examination, such as the direct examination with a magnifying lens and microscopic examination of samples collected with clear cell tape, by superficial and deep skin scrapings and hair plucking and microscopic examination of ear cerumen. In some cases, the diagnostic techniques are not particularly sensitive, and a negative result doesn’t allow ruling out the disease: a therapeutic trial is the only way to confirm or rule out the disease. The recent introduction on the market of new wide-spectrum parasiticidal drugs, effective to prevent flea and tick infestations and with acaricidal and insecticidal activity, will make ectoparasite control much easier. However, for many diseases there are no registered products and standardized protocols for the feline species. Introduction Ectoparasitic skin diseases caused by mites and insects are very important in feline dermatology as they are included in the differential diagnoses of many pruritic dermatological conditions. Their prevalence varies depending on the geographical area F. Leone (*) Clinica Veterinaria Adriatica, Senigallia (Ancona), Italy H. S. Han The Animal Clinic, Singapore © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_19 405 VetBooks.ir 406 F. Leone and H. S. Han considered and on the cat’s lifestyle. Living in colonies of stray cats, breeding facilities or catteries or the potential contact with stray cats make the cat more susceptible to parasitic infestations. Some parasitic diseases may also involve the owner and, although these infestations are usually transient since the parasite is not adapted to man, these zoonoses should not be underestimated. Notoedric Mange Notoedric mange, also known as feline scabies, is a pruritic, contagious skin disease affecting the cat, caused by the mite Notoedres cati. The mite may affect other mammals, including man, and exceptionally the dog [1–3]. The disease prevalence is unknown; it is thought to be rare, however epidemics are still reported in some European countries [3, 4]. Kittens are more prone to the disease compared to adult cats. Morphology Notoedres cati has an oval body, ventrally flattened and dorsally convex; adult females are approximately 225 μm long and males 150 μm long. The head carries a short and squared rostrum. The limbs are short, with unjointed pretarsi ending with a sucker-like structure called pulvillus, present in females only on the two front limb pairs. The hind limbs are rudimental, do not extend beyond the mite’s body, and carry long setae lacking suckers in both sexes (Fig. 1). The dorsal cuticle shows fingerprint-like concentrical rings, transversal rounded scales and no spines. The anal opening is dorsally located and the eggs are oval [4, 5]. Fig. 1 Notoedres cati, adult mite Ectoparasitic Diseases 407 VetBooks.ir Life Cycle The life cycle of Notoedres cati takes place entirely on the host (permanent parasitism). After mating on the skin surface, females burrow tunnels within the stratum corneum at a speed of 2–3 mm/day. Two to three eggs a day are laid in the tunnels for 2–4 weeks. The six-legged larva hatches from the egg, and after two moults as protonymph and tritonymph it becomes an adult mite. The life cycle spans 14–21 days, in favorable environmental conditions. The mite feeds on epidermal debris and interstitial fluid. Epidemiology Notoedric mange is extremely contagious and transmitted by direct contact. For this reason, cats leaving in breeding facilities, catteries or colonies are predisposed. Where feline colonies are maintained, the disease may persist and become established; this happens commonly in urban or extra-urban areas such as cemeteries and ruins, and in close proximity to hospitals and schools [1]. Notoedric mange is a zoonotic disease, and man can transiently be infested, showing pruritus, papules, vesicles and crusts especially on the limbs and trunk. In a study, 63% of people coming into contact with an infested cat showed clinical signs of notoedric mange. Mites were detected by skin scraping in 60% of patients examined [6]. Lesions resolve spontaneously within 3 weeks, once contact with the infected cat is stopped [6, 7]. Clinical Signs Initial lesions are represented by papules or crusted papules and scales, which, with disease progression, evolve into gray-yellow thick crusts, extremely adherent to the skin surface (Fig. 2). Lesions initially appear on the ear pinnae margins and later involve the whole pinna, the face and the neck. With disease progression, the lesions may become generalized. Pruritus is usually severe and self-trauma is common, causing alopecia, erosions and ulcers and predisposing to secondary bacterial or yeast infections [1]. Grooming and the cat’s curled up sleeping habit may cause diffusion to the limbs and perineum. If not treated, the cat may become lethargic and dehydrated and may die in rare cases [1, 8, 9]. Diagnosis Diagnosis requires microscopic identification of the parasite and/or its eggs and/or its feces (round-shaped and brown) in samples collected by superficial skin scraping (Box 1). Mites are usually numerous and can be easily found, as opposite to VetBooks.ir 408 F. Leone and H. S. Han Fig. 2 Crusting of the pinnae margins in a cat with notoedric mange Fig. 3 Superficial skin scraping: adult mites, eggs, and mite feces are present Sarcoptes scabiei (Fig. 3) [1, 8]. Recently, diagnosis of notoedric mange by microscopic examination of samples collected by using clear tape has been reported, with sensitivity comparable to skin scrapings. This technique is less traumatic and therefore indicated for difficult body sites such as lips and periocular regions [10]. Box 1: Superficial Skin Scraping: Practical Tips • Select typical locations of the parasite (e.g., margins of ear pinnae in notoedric mange) • If clipping is necessary, use scissors instead of clippers and leave a few millimeters of hair, to avoid removal of material containing parasites (e.g., crusts) VetBooks.ir Ectoparasitic Diseases 409 • • • • • Apply a few drops of mineral oil on the skin Scrape a large area of skin superficially to avoid blood contamination Perform multiple skin scrapings If a large amount of material is obtained, divide it onto more slides Mix your sample on the glass slide adding a few drops of mineral oil, if necessary, and try to obtain a single layer • Cover with a coverslip and observe the sample with the microscope, closing partially the diaphragm and reducing the light. This allows better visualization of the parasites Treatment Treatment of notoedric mange can be achieved with different acaricidal active ingredients. Registered products include a spot-on formulation containing eprinomectin, fipronil, (S)-methoprene and praziquantel [11] and a spot-on containing moxidectin and imidacloprid [12], which can be applied once or twice at 1-month interval. Other protocols involving active ingredients not registered for the disease involve the use of selamectin spot-on (6–12 mg/kg applied twice at 14 or 30 days’ interval) [1, 13, 14], ivermectin (0.2–0.3 mg/kg subcutaneously at 14 days’ interval) [1, 7, 15] and doramectin (0.2–0.3 mg/kg subcutaneously once) [16]. The new family of isoxazolines ectoparasiticidals has been shown to be effective in other diseases caused by mites. There are no specific studies on feline notoedric mange, but isoxazolines are likely to be effective. Notoedric mange is extremely contagious, and all in-contact cats must be treated to avoid re-infestations. Otodectic Mange Otodectic mange is a parasitic disease of the external ear canal caused by the mite Otodectes cynotis. The mite is not species-specific and may affect cats, dogs and other mammals. Fifty to eighty percent of cases of feline otitis externa is caused by Otodectes cynotis, which is present all over the world [5, 17]. Morphology Otodectes cynotis has an oval body and a long, conical rostrum. Females are 345– 451 μm long, while males are smaller (274–362 μm). The limbs are long, with short pedicles ending with a cup-shaped, sucker-like structure used by the parasite to move quickly within the ear cerumen. The adult mites show sexual dimorphism: males have four pairs of long limbs, ending beyond the body, and smaller abdominal lobes; in females, the fourth pair of legs is atrophic and does not extend beyond the body while abdominal lobes are bigger (Fig. 4). Eggs are oval, slightly flattened on one side and 166–206 μm long [4, 5]. 410 F. Leone and H. S. Han VetBooks.ir Fig. 4 Otodectes cynotis, female mite Life Cycle The life cycle of Otodectes cynotis takes place entirely on the host (permanent parasitism). The mite lives on the surface of the external ear canals and does not burrow. After mating, female mites lay eggs, hatching in 4–6 days. Hexapod larvae actively feed for 3–10 days to moult in octopod protonymphae and then deutonymphae [4, 5]. Mating, often observed during microscopic examination, involves the male mite and the deutonympha: the male mite becomes attached to the deutonympha by using mating suckers and, if a female develops mating occurs, while when a male mite develops there is detachment [4, 8]. The life cycle requires 3 weeks to complete and adult mites survive on the host for approximately 2 months. Mites feed on skin debris and fluids stimulating production of large amounts of ear cerumen, occasionally mixed with blood [8]. Mites can survive for up to 12 days off the host, in ideal temperature conditions [18]. Epidemiology Otodectic mange is extremely contagious and transmission occurs primarily by direct contact with infested cats. Common is also infestation of one ear from the other in the same cat [19]. The disease affects kittens and adults; however, juveniles are predisposed [19]. A temporary infestation of human beings may occur, with papules localized predominantly on the arms and trunk [20], while parasitic otitis is extremely rare [21]. Clinical Signs Otodectic mange causes pruritic, erythematous and ceruminous otitis externa, almost always bilaterally. Otodectic otitis is characterized by large amounts of brown-black dry cerumen, resembling “coffee powder” (Fig. 5) [8]. In felines, VetBooks.ir Ectoparasitic Diseases 411 Fig. 5 Ear cerumen resembling coffee grains, typical of feline otoacariasis hypersensitivity to mites may occur and affected cats show severe pruritus, not proportionate to the number of mites in the ear canal [22]. On the other hand, some cats may have huge numbers of mites in the external ear canal without pruritus, and this may be explained by the absence of hypersensitivity phenomena [4]. Cats infested with Otodectes cynotis may be positive to intradermal testing for house dust mites such as Dermatophagoides farinae, Dermatophagoides pteronyssinus and Acarus siro [23]. Secondary bacterial or yeast infections are possible [24]. Pruritus severity is responsible for auto-traumatic lesions such as alopecia, erosions, ulcers and crusting affecting the preauricular regions, head, face and neck and for otohematomas [17]. Extra-auricular infestation may also occur, since the mite may leave the external ear canal and cause alopecia and miliary dermatitis in other body sites (ectopic mites) [4, 8]. Diagnosis Diagnosis is made by microscopic observation of the mite or its eggs (Fig. 6). The preferred technique is microscopic examination of ear cerumen obtained with an VetBooks.ir 412 F. Leone and H. S. Han Fig. 6 Microscopic examination of ear cerumen: an egg and an adult mite mating with a deutonympha are visualized ear swab (Box 2). Samples must be obtained before applying cerumenolytic products or cleaning the ear canal. To increase the sensitivity of the test, obtaining more samples collected from the horizontal canal by passing the swab through the otoscope cone is recommended. Mites can be visualized by otoscopic examination as white moving dots. Superficial skin scrapings allow to detect mites in cases with extra-auricular localization [4]. Box 2: Microscopic Examination of Ear Cerumen: Practical Tips • Collect your sample from the ear canal with a swab • Collect your sample before applying ceruminolytics or cleaning the ear canal • To collect deeper samples, use the otoscope cone to guide the swab • Dilute the sample in mineral oil, previously applied on a glass slide • Cover with a coverslip and observe the sample on the microscope, closing partially the diaphragm and reducing the light. This allows better visualization of the parasites Treatment Many topical and systemic active ingredients are available to treat otodectic mange. Before treatment, cleaning the ear canals with a cerumenolytic product in order to mechanically remove the parasites and the excess of cerumen caused by the mites is recommended [8]. Topical therapy involves acaricidals such as permethrin or thiabendazole directly applied into the ear canals. These active ingredients have limited residual activity and require daily application for 3 weeks, to ensure that all eggs hatch and emerging larvae are exposed to the drug, despite the fact that they are usually registered to be used for 7–10 days [17, 25]. Otologic products not containing acaricidals are also effective, although their mechanism of action is unclear. It is hypothesized that mites die because they cannot move and/or breathe due to the product [26, 27]. Fipronil spot-on is not registered for otoacariasis; however, it VetBooks.ir Ectoparasitic Diseases 413 proved effective when one drop is applied to each ear canal and the rest between the scapulae [28]. Systemic therapy has many advantages compared to topical therapy. Easiness of administration increases the owner’s compliance to continuity of treatment. Systemic treatment is also effective in cases with ectopic mite localization [17]. Among non-registered active ingredients, ivermectin administered subcutaneously at 0.2–0.3 mg/kg twice at a 14-day interval or orally once weekly for 3 weeks has been shown to be effective [29]. Registered drugs include selamectin and moxidectin-imidacloprid spot-on, both administered twice at 1-month interval [30, 31]. An evidence-based review published in 2016 recommended the use of selamectin or moxidectin-imidacloprid spot-on once or twice at a 30-day interval for feline otodectic mange. There is not enough evidence to recommend other active ingredients [17]. Recently, new active ingredients belonging to the isoxazolines family have been marketed. Sarolaner and selamectin spot-on has been registered to treat otodectic mange and was effective with a single treatment [32]. Also as single treatments, fluralaner alone or in association with moxidectin as spot-on was shown to be effective [33, 34]. Afoxolaner, only registered for dogs, was successfully used in cats as single oral treatment [35]. A single application of a spot-on containing eprinomectin, fipronil, (S)-methoprene, and praziquantel was effective to prevent Otodectes cynotis infestation in cats [36]. Regardless of the treatment chosen, all in-contact animals must be treated due to the likelihood of contagion and presence of asymptomatic carriers [29]. Cheyletiellosis Cheyletiellosis is a parasitic skin disease caused by mites belonging to the genus Cheyletiella. The majority of mites of the Cheyletiellidae family are predators feeding on other mites, while some species are only ectoparasitic. The three species of dermatological interest are Cheyletiella blakei, Cheyletiella yasguri and Cheyletiella parasitivorax [5]. Cheyletiella shows species preference, with Cheyletiella blakei adapted to the cat, Cheyletiella yasguri to the dog and Cheyletiella parasitivorax to the rabbit. However, there is no strict species specificity, and interspecies infestations are possible [4, 8]. Morphology The adult mite is large (300–500 μm long); the body is hexagonal and, according to some authors, resembles a pepper or a shield [4]. The limbs are short and carry comb-like appendixes at the end, the rostrum is well-developed with palps ending with two prominent curved hooks, looking like Viking horns (Fig. 7). The three Cheyletiella species can be differentiated by observing the shape of the sensorial structure (solenidion) located on the third section of the first pair of legs. The solenidion is heart-shaped in Cheyletiella yasguri, conical in Cheyletiella blakei 414 F. Leone and H. S. Han VetBooks.ir Fig. 7 Cheyletiella blakei, adult mite and rounded in Cheyletiella parasitivorax [4, 5]. However, species differentiation is often difficult due to individual variation of the solenidion shape and artifacts due to fixation for microscopy [37]. The eggs are 235–245 μm long and 115–135 μm wide and elliptical and, unlike lice eggs, are non-operculated and loosely attached to hair shafts by thin filaments [4, 8]. Life Cycle The life cycle of Cheyletiella spp. takes place entirely on the host (permanent parasitism). The mite lives in the stratum corneum at the base of hair shafts, moving quickly through the scales without burrowing and feeding on epidermal debris and fluids. The eggs are laid along the hair shafts at 2–3 mm distance from the skin surface. The hexapod larva develops within the egg; once hatched, it moults twice as nymphal stage and finally becomes an adult mite. The life cycle spans 14–21 days, when environmental conditions are favorable [4, 5, 8]. Epidemiology Cheyletiellosis is extremely contagious and transmission is usually by direct contact [4, 8]. Less often, contagion occurs indirectly because adult female mites can survive for up to 10 days in the environment, while immature stages and males die quickly when off the host [4, 8]. Cheyletiella can also be carried by fleas, lice or flies [4]. The disease occurs more commonly in young animals coming from pet shops or colonies while in adult cats can be diagnosed in debilitated or systemically ill animals [5]. Cheyletiellosis is a zoonosis and man can be transiently infested, showing severely pruritic macules and papules on the limbs, VetBooks.ir Ectoparasitic Diseases 415 trunk and buttocks [8, 38, 39]. When the affected animal is treated with an acaricidal, lesions in humans spontaneously regress within 3 weeks [8]. Clinical Signs Clinical signs are of variable severity [8]. Most affected cats initially show exfoliative dermatitis affecting the dorso-lumbar area, with small and dry whitish scales easily detaching from the skin surface (Fig. 8) [4, 8]. The cat’s grooming behavior may remove both the scales and the mites and initially the disease may be slowly progressive and remain undetected [8]. Later on, the exfoliation may become more severe and the hair coat may look “dusty.” Many authors use the term “walking dandruff” to describe the mites moving on the skin surface. Mites are whitish in color and can be distinguished from scales because they move [4, 8]. Pruritus is of variable severity, from absent to severe, and not proportionate to the number of mites, increasing the suspicion of hypersensitivity phenomena in some cats [8, 37, 40]. Some animals present with self-traumatic lesions such as alopecia, excoriations, ulcers and crusts due to severe pruritus [8]. Miliary dermatitis or self-induced alopecia patterns can be observed [8, 29]. Fig. 8 Severe scaling on the dorsum of a cat with cheyletiellosis VetBooks.ir 416 F. Leone and H. S. Han Fig. 9 Cheyletiella egg attached to the hair shaft: the egg is not operculated Diagnosis Diagnosis of cheyletiellosis can be made by microscopic observation of the parasite or its eggs, although the large size of the mite sometimes allows the direct observation on the cat’s hair coat, with a magnifying lens [4, 8]. The preferred technique is microscopic examination of samples obtained with clear cell tape (Box 3). Collection of samples may be done directly on the cat’s fur or after combing the coat with a flea comb. Another useful technique is superficial skin scraping, particularly if few mites are present. Microscopic examination of hair shafts allows observation of eggs attached to hair shafts (Fig. 9) [4, 8, 29, 40, 41]. Pruritic cats may ingest the mites or eggs due to overgrooming and a fecal flotation test may be diagnostic [4, 8, 40]. In feces, Cheyletiella eggs are similar to Ancylostoma eggs; however, they are three to four times bigger (230 × 100 μm) and often embryonated [4, 8]. Identification of mites can be difficult, and in some cases the diagnosis is confirmed by a therapeutic trial [8, 40]. Box 3: Microscopic Examination of Samples Collected with Clear Tape: Practical Tips • Choose good-quality clear tape • Collect your sample applying the tape to the skin multiple times (note: it is possible that parasites are not collected, especially in long-haired cats) • Use the coat combing technique: brush the hair coat with a flea comb or with your hands so the sample falls on the table, which should be perfectly clean • Collect the sample with clear tape directly from the table • Apply a few drops of mineral oil on a glass slide and cover with the clear tape • Cover with a coverslip and observe the sample with the microscope, closing partially the diaphragm and reducing the light. This allows better visualization of the parasites Ectoparasitic Diseases 417 VetBooks.ir Treatment There is no registered active ingredient to treat cheyletiellosis in cats. Topical (fipronil spot-on as a single treatment) [42] or systemic (selamectin spot-on, three applications with 1-month interval [40, 43] or ivermectin, 0.2–0.3 mg/kg subcutaneously once every 2 weeks [41]) acaricidal products have been reported as effective. Trombiculosis Trombiculosis is a parasitic skin disease caused by larvae of mites belonging to the Trombiculidae family. The disease is also called “grass itch mites” or “chiggers” in North America, “scrub itch” in Australia and “harvest mites” in Europe [44]. Within the Trombiculoidea superfamily, the Trombiculidae family includes approximately 1500 species, of which only approximately 50 can infest birds, mammals and man. The most important species of veterinary interest belong to the genus Trombicula, which groups many subgenera such as Neotrombicula and Eutrombicula. In Europe, the most commonly involved species is Neotrombicula autumnalis, while in the Southeastern and Central USA, Eutrombicula alfreddugesi is most often diagnosed [5, 45]. The main feature of this family is that only the larval stage is parasitic (transient parasitism), while nymphae and adult mites are free living in the environment. The larvae are obliged parasites, are not host-specific, and can infest many species including man [4, 5]. Morphology Exapod Neotrombicula autumnalis larvae are oval, 200–400 μm long and are characterized by a typical red-orange color (Fig. 10). The mouth parts include a welldeveloped rostrum and chelicerae with robust tweezer-shaped palps. The trunk carries a pentagonal dorsal scutum (rectangular in Eutrombicula alfreddugesi) and the body is covered by long feather-shaped setae. The limbs end with a trifurcated claw (bifurcated in Eutrombicula alfreddugesi) used to attach to the host [4, 5]. Adult mites are non-parasitic, approximately 1 mm long and are also red-orange in color [4]. Life Cycle The female mite lays spherical eggs on the ground. Larvae emerge from the eggs in a week and move actively on the ground climbing on the grass and waiting for the host [5]. Larvae require 80% relative humidity, and for this reason they climb on plants less than 30 cm high [45]. Once on the host, the larvae attach with the chelicera and feed through a peculiar structure called stilosoma, which is made of solidified mite saliva. This structure allows the buccal apparatus to penetrate down to the VetBooks.ir 418 F. Leone and H. S. Han Fig. 10 Neotrombicula autumnalis hexapod larva; note the bright red-orange color derma of the host and to feed on tissue fluids (extra-intestinal digestion) [4, 46]. During the time spent on the host, the larva grows from 0.25 mm to 0.75 mm, and its bright red-orange color becomes pale yellow [47]. After feeding for 3–15 days, the larvae fall on the ground to complete their life cycle in the environment. The nymphal and adult stages are free living and mobile, and feed on small arthropods or their eggs and fluids from plants. The life cycle spans over 50–70 days and is strongly influenced by the season [4, 5]. Epidemiology In Europe female mites tend to lay eggs in spring and summer and larvae are very abundant at the end of summer and in autumn. However, depending on climate, more than one life cycle can be completed and larvae can also be found in different seasons [4, 48, 49]. Trombiculosis is not a zoonosis because humans get infested directly from the environment; however, direct transmission from animals to man cannot be excluded [47]. People working or spending time in the countryside or in forests during the larvae season are predisposed. Clinical signs are thought to be due to the irritant effect of the mite’s saliva and to acquired hypersensitivity to salivary antigens. In nonsensitized individuals, pruritic macules and papules develop, while in sensitized VetBooks.ir Ectoparasitic Diseases 419 patients the pruritus is severe and associated with urticaria, papules, vesicles, fever and enlarged lymph nodes. Lesions are mostly seen on the wrist, flexural surface of the arm, belt line, ankle, popliteal fossa and thigh [47, 49, 50]. In children, the “summer penile syndrome” is reported: an acute hypersensitivity reaction to mites with erythema, edema, and pruritus to the penis and dysuria due to partial phimosis with reduction of urinary output [51]. Neotrombicula autumnalis larvae are thought to be potential vectors of Borrelia burgdorferi, causing Lyme disease, and Anaplasma phagocytophilum (previously known as Ehrlichia phagocytophila), causing human granulocytic anaplasmosis, by trans-stage or trans-ovaric transmission [52–54]. Clinical Signs Larvae climb on plants and wait for the host, to which they attach by direct contact. For this reason, parasites are preferentially found on body areas in contact with the ground, such as abdomen, interdigital spaces, claw folds, muzzle and pinnae, especially in the fold at the base of the pinnae margin (Henry’s pocket). Mites can be visualized as red-orange aggregates (Fig. 11) [5, 48]. The facial location reflects the first contact site of the larvae with the host, directly linked to the feline exploratory behavior, while Henry’s pocket location might be explained by the epidermal thinness which facilitates the stilosoma formation; moreover, the pocket protects the larvae [48]. In some cats, the infestation is completely asymptomatic, and mites can be incidentally noticed by the owner or observed during the clinical examination for annual vaccination [48]. Other cats show variable pruritus, from moderate to severe, possibly related to individual hypersensitivity which may persist after the larvae abandoned the host [5, 48]. Some cats show crusted papules and self-traumatic lesions such as alopecia, excoriations, ulcers and crusts, depending on pruritus severity. Miliary dermatitis or self-induced alopecia may be observed [48, 55, 56]. Fig. 11 Orange-colored collections of parasitic larvae can be seen to the naked eye on the head and pinna of a cat VetBooks.ir 420 F. Leone and H. S. Han Fig. 12 Superficial skin scraping: many Neotrombicula autumnalis larvae Diagnosis Diagnosis requires a compatible history and macroscopic and microscopic observation of the parasites. Hair coat examination with a magnifying lens allows to observe small aggregates of orange-colored larvae. Microscopic examination of samples collected with clear cell tape or superficial skin scraping allows parasite identification (Fig. 12) [48]. Treatment There is currently no registered treatment for trombiculosis, and there are very few studies on the effectiveness of acaricidals to treat this disease in cats. It is a relatively easy disease to treat, as many ectoparasiticidal products are effective; however, re-infestation may be common in cats with free access to infested areas. Fipronil spray [48, 57], selamectin spot-on [48, 58], and imidacloprid-moxidectin spot-on [48] have been successfully used with a single application. These active ingredients seem to protect against environmental re-infestations. Demodicosis Feline demodicosis is an uncommon to rare parasitic skin disease caused by mites belonging to the genus Demodex. Currently, three species have been identified in cats, using molecular techniques: Demodex cati, Demodex gatoi and a third unnamed species [59, 60]. Ectoparasitic Diseases 421 VetBooks.ir Morphology Demodex cati is very similar to Demodex canis, with minimal taxonomic differences. The body is elongated and cigar-shaped. An adult male is 182 μm long and 20 μm wide, while an adult female is 220 μm long and 30 μm wide [4, 61, 62]. The gnathosoma, in the frontal part of the body, is trapezoidal and carries two chelicera and two palps. In the podosoma, the middle part of the body, there are four pairs of atrophied limbs, each one carrying one pair of tarsal claws, distally bifurcated with a large, caudally oriented dewclaw. The terminal part of the body is the opisthosoma, accounting for two thirds of the mite body, transversally striated and ending with a tapered point (Fig. 13) [61]. The female reproductive system is ventrally located, below the fourth pair of legs. In the male mite, it is in the dorsal half and corresponds to the second pair of legs. The eggs are oval and 70.5 μm long on average [4, 61]. Demodex gatoi is smaller and stubbier and morphologically similar to Demodex criceti, the hamster’s parasite [8, 63]. Males are 90 μm long and females are 110 μm long [62–64]. The opisthosoma accounts for less than half of the total length of the body, is horizontally striated and caudally rounded (Fig. 14) [63, 65]. The eggs are oval and smaller than Demodex cati eggs [63]. Fig. 13 Demodex cati: the opisthosoma accounts for two thirds of the parasite body and the tip is tapered VetBooks.ir 422 F. Leone and H. S. Han Fig. 14 Demodex gatoi: the opisthosoma length is less than half of the entire body and the tip is rounded The third, still unnamed Demodex species is of intermediate size, with a body shorter and stubbier than Demodex cati but longer and more tapered than Demodex gatoi [62, 66, 67]. Life Cycle Demodex cati lives in the hair follicle, often located close to the exit of the sebaceous gland duct, with its head directed downward [61]. Conversely, Demodex gatoi lives in the stratum corneum [62–64]. The environment of the third Demodex species is unknown, since it has never been described in histopathological samples [62, 66]. Information related to the life cycle are referred only to Demodex cati [61]. The life cycle takes place entirely on the host (permanent parasitism). Mating occurs on the skin surface; then the fertilized female moves into the hair follicle where it lays eggs. Six-legged larvae hatch and, after two nymphal stages, the second one moves back onto the skin surface and develops into adult, and more hair follicles are colonized [61]. Ectoparasitic Diseases 423 VetBooks.ir Epidemiology The way of transmission of Demodex cati is unknown. In the dog, transmission occurs from the mother to puppies within the first days of life, during lactation [8]. The morphologic and environmental similarities of Demodex canis and Demodex cati suggest that the way of transmission is identical. The disease is not contagious. The disease caused by Demodex gatoi appears to be contagious among cats sharing the same environment, if there is enough parasitic pressure [64, 66, 68]. It is not known if the third Demodex species is contagious. Demodex spp. are host-specific mites and the disease is not zoonotic. Clinical Signs In Demodex cati demodicosis, a localized and a generalized form have been described [4, 8]. The localized form involves the head and neck, particularly the periorbital and perilabial regions and the chin [4, 8, 69]. The lesions are erythema, alopecia, scales and crusts. Pruritus is variable, generally mild to absent [8, 69–71]. When the disease involves the external ear canal, it causes a bilateral ceruminous otitis which is often reported in feline immunodeficiency virus (FIV)-positive cats [72, 73]. A localized form has also been reported in cats affected by asthma and chronically treated with glucocorticoids administered with aerosol [74]. The generalized form causes lesions similar to the ones observed in the localized form, but more severe and extensive, involving the muzzle, neck, trunk and limbs or the whole body (Fig. 15) [8, 65, 69–71]. The generalized disease is often associated with immunosuppressive therapies or concurrent systemic diseases Fig. 15 Large alopecic area on the dorsum of a cat with generalized demodicosis due to Demodex cati VetBooks.ir 424 F. Leone and H. S. Han Fig. 16 Severe selfinduced lesions in a cat with Demodex gatoi such as diabetes mellitus, xanthomas, toxoplasmosis, systemic lupus erythematosus, hypercortisolism, retroviral infections and Bowenoid in situ carcinoma [69, 71, 75–79]. However, in some cases an underlying disease cannot be identified [80]. In Demodex gatoi infestation, the most common clinical sign is variable pruritus, from absent to severe, and in some cases mite hypersensitivity is suspected (Fig. 16) [8, 62, 64, 81]. Cats may show self-induced alopecia involving the trunk, abdomen flanks or limbs or self-traumatic lesions such as alopecia, excoriations, ulcers and crusts or papular and crusting dermatitis (miliary dermatitis) [64, 81]. This type of demodicosis is not associated with immunosuppression [81]. Infestation with different Demodex species in the same cat has been reported [62, 65]. Diagnosis Diagnosis of feline demodicosis is confirmed by microscopic observation of the adult mite, its immature stages, or its eggs. Diagnostic techniques used are different depending on the involved mite species and its localization. Demodex cati lives in the hair follicle, and the preferred diagnostic method is the deep skin scraping, followed by microscopic examination of hair pluckings (Boxes 4 and 5) [81]. For Demodex gatoi, a superficially located species, the suggested methods are superficial skin scrapings or microscopic examination of samples obtained by clear cell tape [81]. These mites are small and transparent, and reducing the amount of light going through the microscope by partially closing the diaphragm to increase contrast is advised [64, 65]. In overgrooming cats, the observation of Demodex gatoi may be difficult, and some authors suggest a fecal examination with flotation [81, 82]. Moreover, some authors suggest to treat cats with an acaricidal whenever Demodex gatoi is suspected [64, 81]. VetBooks.ir Ectoparasitic Diseases 425 Box 4: Microscopic Examination of Hair Pluckings: Practical Tips • • • • • Carefully choose the hair shafts to examine Use hemostats or your fingers to grab the hair base Pluck the hair in the direction of growth Align the hair shafts on a glass slide with a few drops of mineral oil Cover with a coverslip and observe the sample on the microscope, closing partially the diaphragm and reducing the light. This allows better visualization of the parasites Box 5: Deep Skin Scrapings: Practical Tips • • • • • • • Choose your sample spot, avoiding ulcerated or fibrotic areas Clip hair if required Apply a few drops of mineral oil to the skin Scrape the skin until capillary bleeding is observed Perform multiple skin scrapings If a large amount of material is obtained, divide it onto more slides Mix your sample on the glass slide adding a few drops of mineral oil if necessary and try to obtain a single layer • Cover with a coverslip and observe the sample on the microscope, closing partially the diaphragm and reducing the light. This allows better visualization of the parasites Treatment There is no registered product for feline demodicosis and there are no standardized protocols. Various active ingredients have been used with variable results, depending on the mite species and the dosage administered. An evidence-based review recommended the use of weekly rinses with 2% calcium sulfur [83]; however, this product is not available in many countries. Moderate evidence of effectiveness for both Demodex species was reported for once or twice weekly amitraz rinses (0.0125–0.025%), which may be toxic in felines, and for macrocyclic lactones [83]. Ivermectin may be administered both orally and subcutaneously and is effective for both species; however, failures have been reported in Demodex gatoi cases [62, 64, 81]. Doramectin (600 μg/kg subcutaneously once weekly for 2–3 weeks) is effective to treat Demodex cati [83, 84]. Both with ivermectin and doramectin, severe central nervous system toxicity has been described [62]. Milbemycin oxime has been shown to be effective against Demodex cati at 1–1.5 mg/kg orally once daily for 2–7 months [74, 76], and once weekly topical imidacloprid/moxidectin for eight applications is effective against Demodex gatoi [85]. VetBooks.ir 426 F. Leone and H. S. Han Recently, single treatment with oral fluralaner has been reported to be effective for both Demodex species [86, 87]. Demodex gatoi is contagious and treatment of all in-contact cats is recommended [8]. Pediculosis Pediculosis is a lice infestation. Lice are small, wingless insects, 0.5–8 mm long, dorso-ventrally flattened, with legs carrying strong claws to attach to the hair shafts [4, 88]. The majority of mammals, including man and birds and excluding monotremes and bats, are infested by at least one lice species [88]. As other insects, their body is segmented with head, thorax and abdomen; they have three pair of legs and one pair of antennae. They spend their whole life on the host and are highly host-specific, and many species have preferred body locations. The majority of lice belong to the suborder Anoplura, or sucking lice, infesting only placented mammals and to suborder Ischnocera, previously called Mallophaga, biting lice infesting mammals and birds. Sucking lice have a specialized buccal apparatus for sucking blood, while biting lice do not feed on blood but on epidermal debris and hair [4, 88]. Felicola subrostratus is the only lice infesting cats. Morphology Felicola subrostratus is a biting louse (suborder Ischnocera) 1–1.5 mm long, and its color is beige-yellowish with transverse dark bands. The head is wider than the chest and its shape is pentagonal and frontally pointed. On the ventral surface, the louse shows a longitudinal, median cleft adapted to the hair shaft. The antennae are similar in both sexes and comprised of three segments. The buccal apparatus is welldeveloped and helps the lice to remain attached to the hair shaft (Fig. 17). The legs are short, ending with a single claw [88]. Fig. 17 Felicola subrostratus, adult louse Ectoparasitic Diseases 427 VetBooks.ir Life Cycle The life cycle takes place entirely on the host (permanent parasitism), where the female lays operculated eggs strongly attached to the hair shafts. A nymph emerges from the egg and three moults are required to become adult. The juvenile stages are similar to the adults, but smaller and sexually immature with undeveloped gonads (uncomplete metamorphosis). The whole cycle requires 2–3 weeks, and a female can lay up to 200–300 eggs in its life, which lasts for approximately 1 month [88]. Compared to other insects, lice do not have a high reproductive index; however, females during ovodeposition produce a sticky liquid which becomes solid, cementing the egg for all its length excluding the operculus (breathing opening) to the hair shaft. This reduces the loss of eggs and mortality of immature stages and increases the lice population on the host [88]. Epidemiology Lice cannot survive for more than 1–2 days off the host and generally spend all their lives on the same host. Transmission occurs by direct contact between infested and susceptible cats, since lice leave their host only to move to another one [88]. Being highly host-specific, transmission occurs only among cats. In temperate climates, seasonal fluctuation with winter increase of infestations is reported, possibly due to the host hair coat characteristics. Long-haired cats are predisposed; however, the most severe cases are seen in malnourished cats or cats living in poor hygienic conditions [8, 88]. Clinical Signs Lice can infest the whole body, with preferred localization on the head, neck and dorso-lumbar region [88]. Lesions observed on the cat vary depending on the number of parasites and severity of pruritus, which is absent to moderate [8, 88]. Some cats are asymptomatic: lice can be observed moving on the hair shafts and often only eggs can be seen, attached to the hair shafts and macroscopically similar to scales. Eggs can be correctly identified by their oval shape and whitish color on closer examination. The hair coat may appear dull, unkempt, and dirty (Fig. 18) [8]. In other cases, primary lesions such as papules and scaling may be seen, or selftraumatic secondary lesions (excoriations, crusts), self-induced alopecia or miliary dermatitis [8]. Diagnosis Lice and their eggs are easily identified by close observation or using a magnifying lens. Microscopic examination of hair shafts and samples collected with clear VetBooks.ir 428 F. Leone and H. S. Han Fig. 18 Lice infestation in a cat: the hair coat is dull and unkempt and looks dirty Fig. 19 Operculated louse egg firmly attached to the hair shaft cell tape confirm the diagnosis [8]. Hair combing is also useful to collect samples from the examination table. When no adult lice are found, but just eggs, these must be differentiated from Cheyletiella spp. eggs, also attached to hair shafts. Lice eggs are much bigger than Cheyletiella eggs and the operculus is dorsal (Fig. 19). Moreover, lice eggs are attached for two thirds of their length to the hair shafts, while Cheyletiella eggs are loosely fixed by thin fibrils. Treatment Lice are susceptible to the majority of insecticides in the market [8]. Currently, registered active ingredients to treat feline pediculosis include fipronil (spot-on and spray) [89] and selamectin spot-on [90], recently made available also in association with sarolaner. A single treatment is recommended with all these products; however, eggs are resistant to the majority of insecticides. It is advisable repeating the VetBooks.ir Ectoparasitic Diseases 429 treatment after 14 days to ensure that lice emerged from eggs after the first treatment are killed. Treatment must be extended to all in-contact cats [8, 88]. Lynxacariosis Lynxacarus radovskyi (feline fur mites) are astigmatid mites of the Listrophoridae family which houses small long mites specialized for grasping of the hairs of mammals. Other notable fur mites include Chirodiscoides caviae and Leporacarus gibbus which infests the guinea pig and rabbit respectively. Lynxacarus radovskyi is characterized by a laterally compressed body, short anterior legs and has a characteristic ability to grasp the hair shaft using a modified specialized clasping structure comprised of the propodosomal flaps and palp coxae. Its legs terminate in ambulacral discs which are membraneous structures bearing remnants of claw that facilitates maximal contact for hair grasping. The male of the species possesses large anal suckers used to fasten onto the female during copulation. The female then lays eggs that hatch into six-legged larvae and then eight-legged nymphs, which finally moult into an adult mite (Fig. 20). Lynxacarus radovskyi feed on shed corneocytes, fungal spores, sebum and also pollen on the host. Exact life cycle has not been fully described and transmission is through direct contact. The mite has been reported in southern parts of the USA (Texas, Florida), Australia, New Zealand, New Caledonia, French Guyana, Caribbean, Fiji, Malaysia, Philippines, India, Singapore and also South America, but its incidence is thought to be under reported. Lynxacarus radovskyi is not zoonotic to humans or any other species except Felis catus. Clinical Signs Most infested cats are asymptomatic, but reports of a pathological response from susceptible host have been reported. In these cats, a self-induced, non-inflammatory, caudally directed alopecia has been described. Alopecia typically begins from Fig. 20 A typical hair pluck demonstrating a female nymph of Lynxacarus radovskyi and an egg VetBooks.ir 430 F. Leone and H. S. Han Fig. 21 A cat with lynxacariosis, presented with bilaterally symmetrical, noninflammatory, self-induced alopecia the perineum/tail base where the mites are thought to be most commonly isolated before spreading to the lateral thighs, abdomen, and flanks (Fig. 21) [91]. Infested cats are often presented with increased scale production and a dry, dull coat with easily epilated hairs. Other extracutaneous signs such as gingivitis, gastrointestinal disturbances (hairballs) and restlessness due to irritation may also be seen. As the mite can cause extracutaneous signs, it is important that attending veterinarians consider this parasite as a possible differential diagnosis, especially when these extracutaneous signs are present. Diagnosis The parasites can be detected via microscopic examination of hair plucks or adhesive tape technique obtained from the perineum, lateral hind limbs or cervical region where they are more readily observed [91]. Mites are easily demonstrated in overt heavy infestation but may be difficult to demonstrate in a patient that excessively self-grooms. Treatment The parasite is sensitive to all acaricidals. Published efficacy reports include fipronil, moxidectin plus imidacloprid and fluralaner [92, 93]. Topical selamectin, administered every fortnightly, is equally effective. Feline Cutaneous Screwworm Myiasis Myiasis is defined as the invasion of a living vertebrate animal by fly larvae, which may or may not be associated with feeding on the host tissue [94]. In cases of obligatory myiasis, fly species such as New-World screwworm (NWS) Cochliomyia hominivorax or the Old-World screwworm (OWS) Chrysomya bezziana lay their eggs on a living host regardless of species, and the disease they cause is referred to as cutaneous screwworm myiasis. Historically, the range of NWS extended from Ectoparasitic Diseases b VetBooks.ir a 431 Fig. 22 (a) A cat presented with an exudative, ulcerative, swollen and erythematous wound at the base of the left ear, with characteristic putrid smell. (b) Upon closer inspection, burrowing larvae are clearly visualized within these lesions the southern states of the USA, through Mexico, Central america, the Caribbean and northern countries of South America to Uruguay, northern Chile and northern Argentina. Its distribution contracts during the winter months and expanded during summer months, thus producing a seasonality at its edges and year round incidence in the central areas. With the successful implementation of sterile insect technique (SIT), NWS has been eradicted from USA, Mexico, Curacao, Puerto Rico, extending to Central American countries such as Guatemala, Belize, El Salvador, Honduras, Nicaragua to Panama. OWS, as the name suggest is confined to the Old World which includes much of Africa (from Ethiopia and sub-Saharan countries to northern South Africa), Middle East Gulf region, the Indian subcontinent and south east Asia (Malaysia, Singapore, Indonesia, Philipines to Papua New Guinea). OWS has recently been reported in Hong Kong and the southern autonomous region of Guangxi, in mainland China [95]. Clinical Signs Female flies of Cochliomyia hominivorax and Chrysomya bezziana typically lay their eggs at wound edges. Eggs hatch within 12–24 hours. As the name screwworm suggests, the hatched larvae burrow or screw themselves head facing downward into host tissue and begin feeding. This results in exudative and ulcerative lesions with easily visualized maggots within the lesions, emanating a characteristic putrid odor (Figs. 22a, b). These foul putrid wounds then attract more oviposition, resulting in superinfestation that can lead to death due to sepsis in the untreated host. After approximately 7 days of feeding, the larvae drop onto the ground, burrow and pupate, and adult flies emerge from the puparium in approximately 7 days. Adult, intact male domestic short hair cats are predisposed to develop screwworm myiasis VetBooks.ir 432 F. Leone and H. S. Han from inter-cat aggression, with some concurrently diagnosed with sporotrichosis in regions where these two diseases are reported. The most common sites for screwworm myiasis in the cats are the paws, followed by the tail and perineum [96]. Judging from the severity of tissue destruction, one would reasonably expect that the host-parasite relationship will be highlighted by the quick removal of these larvae by the fastidiously grooming host. However, the ability of the larvae to induce a state of immune supression renders the host extremely tolerant of the infestation and thus some patients are presented for medical attention in advanced stages of infestation. Treatment Nitenpyram (Capstar®, Elanco, IL, USA) at standard packaging dose, administered as recommended by manufacturer (with or without food), is the most common treatment modality in countries where the drug is available. Larvicidal efficacy is thought to range between 94.1% to 100% within 24 hours in dogs treated with nitenpyram with scarce data from cats [97–99]. Once the larvae have died, they are manually removed, the wound is debrided, and if no larvae are left inside the wound (foreign body), the wound typically heals quickly. In regions where nitenpyram is not available, extralabel use of systemic/topical ivermectin (0.3–0.6 mg/kg) and/or topical powder-based insecticides marketed for the treatment of cutaneous myiasis in farm animals, consisting of coumaphos, propoxur, and sulphanilamide (Negasunt™ Dusting Powder, Bayer Pharmaceuticals, Maharashtra, India), are used. There are very limited treatment options available for veterinarians to treat feline cutaneous myiasis other than nitenpyram. Due to this limitation, many cats are still treated with extra-label use of ivermectin and carbamates, originally meant for farm use. References 1. Leone F, Albanese F, Fileccia I. Feline notoedric mange: a report of 22 cases. Prat Méd Chir Anim Comp. 2003;38:421–7. 2. Leone F. Canine notoedric mange. Vet Dermatol. 2007;18(2):127–9. 3. Foley J, Serieys LE, Stephenson N, et al. A synthetic review of notoedres species mites and mange. Parasitology. 2016;9:1–15. 4. Bowman DD, Hendrix CM, Lindsay, et al. The Arthropods. In: Bowman D, editor. Feline Clinical Parasitology. Ames: Iowa State University Press; 2002. p. 355–455. 5. Wall R, Shearer D. Mites (Acari). In: Veterinary Ectoparasites: biology, pathology & control. 2nd ed. Oxford: Blackwell Science; 2001. p. 23–54. 6. Chakrabarti A. Human notoedric scabies from contact with cats infested with Notoedres cati. Int J Dermatol. 1986;25(10):646–8. 7. Foley RH. A notoedric mange epizootic in an island’s cat population. Feline Pract. 1991;19:8–10. 8. Miller WH, Griffin CE, Campbell KL. Parasitic skin disease. In: Muller and Kirk’s small animal dermatology. 7th ed. St. Louis: Elsevier Mosby; 2013. p. 284–342. 9. Leone F, Albanese F, Fileccia I. Epidemiological and clinical finding of notoedric mange in 30 cats. Vet Dermatol. 2005;16(5):359. 10. Sampaio KO, de Oliveira LM, Burmann PM, et al. Acetate tape impression test for diagnosis of notoedric mange in cats. J Feline Med Surg. 2016;15:1–4. 11. Knaus M, Capári B, Visser M. Therapeutic efficacy of Broadline against notoedric mange in cats. Parasitol Res. 2014;113(11):4303–6. VetBooks.ir Ectoparasitic Diseases 433 12. Hellmann K, Petry G, Capari B, et al. Treatment of naturally Notoedres cati-infested cats with a combination of imidacloprid 10%/moxidectin 1% spot-on (advocate®/advantage® multi, Bayer). Parasitol Res. 2013;112(Suppl 1):57–66. 13. Itoh N, Muraoka N, Aoki M, et al. Treatment of Notoedric cati infestation in cats with selamectin. Vet Rec. 2004;154(13):409. 14. Fisher MA, Shanks DJ. A review of the off-label use of selamectin (stronghold/revolution) in dogs and cats. Acta Vet Scand. 2008;50:46. 15. Sivajothi S, Sudhakara Reddy B, et al. Notoedres cati in cats and its management. J Parasit Dis. 2015;39(2):303–5. 16. Delucchi L, Castro E. Use of doramectin for treatment of notoedric mange in five cats. J Am Vet Med Assoc. 2000;216(2):215–6. 17. Yang C, Huang HP. Evidence-based veterinary dermatology: a review of published studies of treatments for Otodectes cynotis (ear mite) infestation in cats. Vet Dermatol. 2016;27(4):221–e56. 18. Otranto D, Milillo P, Mesto P, et al. Otodectes cynotis (Acari: Psoroptidae): examination of survival off-the-host under natural and laboratory conditions. Exp Appl Acarol. 2004;32(3):171–9. 19. Sotiraki ST, Koutinas AF, Leontides LS, et al. Factors affecting the frequency of ear canal and face infestation by Otodectes cynotis in the cat. Vet Parasitol. 2001;96(4):309–15. 20. Herwick RP. Lesions caused by canine ear mites. Arch Dermatol. 1978;114(1):130. 21. Lopez RA. Of mites and man. J Am Vet Med Assoc. 1993;203(5):606–7. 22. Powell MB, et al. Reaginic hypersensitivity in Otodectes cynotis infestation of cats and mode of mite feeding. Am J Vet Res. 1980;41(6):877–82. 23. Saridomichelakis MN, Koutinas AF, Gioulekas D, et al. Sensitization to dust mites in cats with Otodectes cynotis infestation. Vet Dermatol. 1999;10(2):89–94. 24. Roy J, Bédard C, Moreau M, et al. Comparative short-term efficacy of Oridermyl(®) auricular ointment and revolution(®) selamectin spot-on against feline Otodectes cynotis and its associated secondary otitis externa. Can Vet J. 2012;53(7):762–6. 25. Ghubash R. Parasitic miticidal therapy. Clin Tech Small Anim Pract. 2006;21(3):135–44. 26. Scherk-Nixon M, Baker B, Pauling GE, et al. 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Efficacy of a new spot-on formulation of selamectin plus sarolaner in the treatment of Otodectes cynotis in cats. Vet Parasitol. 2017;238(Suppl 1):S27–30. 33. Taenzler J, de Vos C, Roepke RK, et al. Efficacy of fluralaner against Otodectes cynotis infestations in dogs and cats. Parasit Vectors. 2017;10(1):30. 34. Taenzler J, de Vos C, Roepke RKA, et al. Efficacy of fluralaner plus moxidectin (Bravecto® plus spot-on solution for cats) against Otodectes cynotis infestations in cats. Parasit Vectors. 2018;11(1):595. 35. Machado MA, Campos DR, Lopes NL, et al. Efficacy of afoxolaner in the treatment of otodectic mange in naturally infested cats. Vet Parasitol. 2018;256:29–31. 36. Beugnet F, Bouhsira E, Halos L, et al. Preventive efficacy of a topical combination of fipronil – (S)-methoprene – eprinomectin – praziquantel against ear mite (Otodectes cynotis) infestation of cats through a natural infestation model. Parasite. 2014;21:40. 37. Schmeitzel LP. Cheyletiellosis and scabies. Vet Clin North Am Small Anim Pract. 1988;18(5):1069–76. VetBooks.ir 434 F. Leone and H. S. Han 38. Lee BW. Cheyletiella dermatitis: a report of fourteen cases. Cutis. 1991;47(2):111–4. 39. Wagner R, Stallmeister N. Cheyletiella dermatitis in humans, dogs and cats. Br J Dermatol. 2000;143(5):1110–2. 40. Chailleux N, Paradis M. Efficacy of selamectin in the treatment of naturally acquired cheyletiellosis in cats. Can Vet J. 2002;43(10):767–70. 41. Paradis M, Scott D, Villeneuve A. Efficacy of ivermectin against Cheyletiella blakei infestation in cats. J Am Anim Hosp Assoc. 1990;26(2):125–8. 42. Scarampella F, Pollmeier M, Visser M, et al. Efficacy of fipronil in the treatment of feline cheyletiellosis. Vet Parasitol. 2005;129(3–4):333–9. 43. Fisher MA, Shanks DJ. A review of the off-label use of selamectin (stronghold/revolution) in dogs and cats. Acta Vet Scand. 2008;50:46. 44. Takahashi M, Misumi H, Urakami H, et al. Trombidiosis in cats caused by the bite of the larval trombiculid mite Helenicula miyagawai (Acari: Trombiculidae). Vet Rec. 2004;154(15):471. 45. McClain D, Dana AN, Goldenberg G. Mite infestations. Dermatol Ther. 2009;22(4):327–46. 46. Shatrov AB. Stylostome formation in trombiculid mites (Acariformes: Trombiculidae). Exp Appl Acarol. 2009;49(4):261–80. 47. Caputo V, Santi F, Cascio A, et al. Trombiculiasis: an underreported ectoparasitosis in Sicily. Infez Med. 2018;26(1):77–80. 48. Leone F, Di Bella A, Vercelli A, et al. Feline trombiculosis: a retrospective study in 72 cats. Vet Dermatol. 2013;24(5):535–e126. 49. Guarneri C, Chokoeva AA, Wollina U, et al. Trombiculiasis: not only a matter of animals! Wien Med Wochenschr. 2017;167(3–4):70–3. 50. Guarneri F, Pugliese A, Giudice E, et al. Trombiculiasis: clinical contribution. Eur J Dermatol. 2005;15(6):495–6. 51. Smith GA, Sharma V, Knapp JF, et al. The summer penile syndrome: seasonal acute hypersensitivity reaction caused by chigger bites on the penis. Pediatr Emerg Care. 1998;14(2):116–8. 52. Fernández-Soto P, Pérez-Sánchez R, Encinas-Grandes A. Molecular detection of Ehrlichia phagocytophila genogroup organisms in larvae of Neotrombicula autumnalis (Acari: Trombiculidae) captured in Spain. J Parasitol. 2001;87(6):1482–3. 53. Kampen H, Schöler A, Metzen M, et al. Neotrombicula autumnalis (Acari, Trombiculidae) as a vector for Borrelia burgdorferi sensu lato? Exp Appl Acarol. 2004;33(1–2):93–102. 54. Literak I, Stekolnikov AA, Sychra O, et al. Larvae of chigger mites Neotrombicula spp. (Acari: Trombiculidae) exhibited Borrelia but no Anaplasma infections: a field study including birds from the Czech Carpathians as hosts of chiggers. Exp Appl Acarol. 2008;44(4):307–14. 55. Leone F, Cornegliani L, Vercelli A. Clinical findings of trombiculiasis in 50 cats. Vet Dermatol. 2010;21(5):538. 56. Fleming EJ, Chastain CB. Miliary dermatitis associated with Eutrombicula infestation in a cat. J Am Anim Hosp Assoc. 1991;27:529–31. 57. Nuttall TJ, French AT, Cheetham HC, et al. Treatment of Trombicula autumnalis infestation in dogs and cats with a 0.25 per cent fipronil pump spray. J Small Anim Pract. 1998;39(5):237–9. 58. Leone F, Albanese F. Efficacy of selamectin spot-on formulation against Neotrombicula autumnalis in eight cats. Vet Dermatol. 2004;15(Suppl.1):49. 59. Frank LA, Kania SA, Chung K, et al. A molecular technique for the detection and differentiation of Demodex mites on cats. Vet Dermatol. 2013;24(3):367–9. e82–e3 60. Ferreira D, Sastre N, Ravera I, et al. Identification of a third feline Demodex species through partial sequencing of the 16S rDNA and frequency of Demodex species in 74 cats using a PCR assay. Vet Dermatol. 2015;26(4):239–e53. 61. Desch C, Nutting WB. Demodex cati Hirst 1919: a redescription. Cornell Vet. 1979;69(3):280–5. 62. Löwenstein C, Beck W, Bessmann K, et al. Feline demodicosis caused by concurrent infestation with Demodex cati and an unnamed species of mite. Vet Rec. 2005;157(10):290–2. 63. Desch CE Jr, Stewart TB. Demodex gatoi: new species of hair follicle mite (Acari: Demodecidae) from the domestic cat (Carnivora: Felidae). J Med Entomol. 1999;36(2):167–70. 64. Saari SA, Juuti KH, Palojärvi JH, et al. Demodex gatoi-associated contagious pruritic dermatosis in cats – a report from six households in Finland. Acta Vet Scand. 2009;51:40. 65. Neel JA, Tarigo J, Tater KC, et al. Deep and superficial skin scrapings from a feline immunodeficiency virus-positive cat. Vet Clin Pathol. 2007;36(1):101–4. VetBooks.ir Ectoparasitic Diseases 435 66. Kano R, Hyuga A, Matsumoto J, et al. Feline demodicosis caused by an unnamed species. Res Vet Sci. 2012;92(2):257–8. 67. Moriello KA, Newbury S, Steinberg H. Five observations of a third morphologically distinct feline Demodex mite. Vet Dermatol. 2013;24(4):460–2. 68. Morris DO. Contagious demodicosis in three cats residing in a common household. J Am Anim Hosp Assoc. 1996;32(4):350–2. 69. Guaguere E, Muller A, Degorce-Rubiales F. Feline demodicosis: a retrospective study of 12 cases. Vet Dermatol. 2004;15(Suppl 1):34. 70. Stogdale L, Moore DJ. Feline demodicosis. J Am Anim Hosp Assoc. 1982;18:427–32. 71. Medleau L, Brown CA, Brown SA, et al. Demodicosis in cats. J Am Anim Hosp Assoc. 1988;24:85–91. 72. Kontos V, Sotiraki S, Himonas C. Two rare disorders in the cat: Demodectic otitis externa and Sarcoptic mange. Feline Pract. 1998;26(6):18–20. 73. Van Poucke S. Ceruminous otitis externa due to Demodex cati in a cat. Vet Rec. 2001;149(21):651–2. 74. Bizikova P. Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids. Vet Dermatol. 2014;25(3):222–5. 75. White SD, Carpenter JL, Moore FM, et al. Generalized demodicosis associated with diabetes mellitus in two cats. J Am Vet Med Assoc. 1987;191(4):448–50. 76. Vogelnest LJ. Cutaneous xanthomas with concurrent demodicosis and dermatophytosis in a cat. Aust Vet. 2001;79(7):470–5. 77. Zerbe CA, Nachreiner RF, Dunstan RW, et al. Hyperadrenocorticism in a cat. J Am Vet Med Assoc. 1987;190(5):559–63. 78. Chalmers S, Schick RO, Jeffers J. Demodicosis in two cats seropositive for feline immunodeficiency virus. J Am Vet Med Assoc. 1989;194(2):256–7. 79. Guaguère E, Olivry T, Delverdier-Poujade A, et al. Demodex cati infestation in association with feline cutaneous squamous cell carcinoma in situ: a report of five cases. Vet Dermatol. 1999;10(1):61–7. 80. Bailey RG, Thompson RC, Nickels DG. Demodectic mange in a cat. Aust Vet J. 1981;57(1):49. 81. Beale K. Feline demodicosis: a consideration in the itchy or overgrooming cat. J Feline Med Surg. 2012;14(3):209–13. 82. Silbermayr K, Joachim A, Litschauer B, et al. The first case of Demodex gatoi in Austria, detected with fecal flotation. Parasitol Res. 2013;112(8):2805–10. 83. Mueller RS. Treatment protocols for demodicosis: an evidence-based review. Vet Dermatol. 2004;15(2):75–89. 84. Johnstone IP. Doramectin as a treatment for canine and feline demodicosis. Aust Vet Pract. 2002;32(3):98–103. 85. Short J, Gram D. Successful treatment of Demodex gatoi with 10% Imidacloprid/1% Moxidectin. J Am Anim Hosp Assoc. 2016;52(1):68–72. 86. Matricoti I, Maina E. The use of oral fluralaner for the treatment of feline generalised demodicosis: a case report. J Small Anim Pract. 2017;58(8):476–9. 87. Duangkaew L, Hoffman H. Efficacy of oral fluralaner for the treatment of Demodex gatoi in two shelter cats. Vet Dermatol. 2018;29(3):262. 88. Wall R, Shearer D. Lice. In: Veterinary Ectoparasites: biology, pathology & control. 2nd ed. Oxford: Blackwell Science; 2001. p. 162–78. 89. Pollmeier M, Pengo G, Longo M, et al. Effective treatment and control of biting lice, Felicola subrostratus (Nitzsch in Burmeister, 1838), on cats using fipronil formulations. Vet Parasitol. 2004;121(1–2):157–65. 90. Shanks DJ, Gautier P, McTier TL, et al. Efficacy of selamectin against biting lice on dogs and cats. Vet Rec. 2003;152(8):234–7. 91. Ketzis JK, Dundas J, Shell LG. Lynxacarus radovskyi mites in feral cats: a study of diagnostic methods, preferential body locations, co-infestations and prevalence. Vet Dermatol. 2016;27:425–e108. 92. Clare F, Mello RMLC. Use of fipronil for treatment of Lynxacarus radovskyi in outdoor cats in Rio de Janeiro (Brazil). Vet Dermatol. 2004;15(Suppl 1):50. (abstract) VetBooks.ir 436 F. Leone and H. S. Han 93. Han HS, Noli C, Cena T. Efficacy and duration of action of oral fluralaner and spot-on moxidectin/imidacloprid in cats infested with Lynxacarus radovskyi. Vet Dermatol. 2016;27:474–e127. 94. Catts EP, Mullen G. Myiasis (Muscoidea, Oestroidea). In: Mullen G, Durden L, editors. Medical and veterinary entomology. Orlando: Academic Press; 2002. p. 317–43. 95. Fang Fang, Qinghua Chang, Zhaoan Sheng, Yu Zhang, Zhijuan Yin, Jacques Guillot, Chrysomya bezziana: a case report in a dog from Southern China and review of the Chinese literature. Parasitology Research. 96. Hock Siew Han, Peik Yean Toh, Hock Binn Yoong, Hooi Meng Loh, Lee Lee Tan, Yin Yin Ng, (2018) Canine and feline cutaneous screw-worm myiasis in Malaysia: clinical aspects in 76 cases. Vet Dermatol. 29(5):442–e148. 97. Clarissa P de Souza, Guilherme G. Verocai, Regina HR Ramadinha, (2010) Myiasis caused by the New World screwworm fly (Diptera: Calliphoridae) in cats from Brazil: report of five cases. J Feline Med Surg. 12(2):166–8. 98. Thaís R. Correia, Fabio B. Scott, Guilherme G. Verocai, Clarissa P. Souza, Julio I. Fernandes, Raquel M.P.S. Melo, Vanessa P.C. Vieira, Francisco A. Ribeiro, (2010) Larvicidal efficacy of nitenpyram on the treatment of myiasis caused by Cochliomyia hominivorax (Diptera: Calliphoridae) in dogs. Vet Parasitol. 173(1–2):169–72. 99. Hock Siew Han, Charles Chen, Carlo Schievano, Chiara Noli, (2018) The comparative efficacy of afoxolaner, spinosad, milbemycin, spinosad plus milbemycin, and nitenpyram for the treatment of canine cutaneous myiasis. Vet Dermatol. 29(4):312–e109. VetBooks.ir Flea Biology, Allergy and Control Chiara Noli Abstract Fleas are the most common ectoparasites and flea-bite allergy can develop in cats. The clinical signs are represented by pruritus, excoriations, self-induced alopecia, manifestations of the eosinophilic granuloma complex and miliary dermatitis, which often, but not exclusively, involves the caudal dorsal and ventral part of the body. The diagnosis is obtained with the clinical presentation and response to flea control. Flea control is based on adulticides, which kill adult fleas on the cat, and insect growth regulators (IGR), which inhibit the development of pre-adult stages in the environment. Introduction The flea species most frequently identified in cats is Ctenocephalides felis felis (Fig. 1). A comprehensive review on its biology and ecology has recently been published [1]. Fleas can be a cause and/or vector of a variety of diseases such as anemia in heavily infested kittens, tapeworm infestations, Lyme disease, pest, viruses, hemoparasites, cat-scratch disease and flea allergy [1, 2]. Recognition of some of these conditions, such as tapeworm in the cat or cat-scratch disease in the owner, is a sign of flea infestation, even if asymptomatic in the feline carrier host. Flea-bite allergy is by far the most frequent disease caused by fleas in cats and its prevalence depends on the geographical region and local parasite prevention habits. In a recent multicenter European study, flea-bite allergy was found to account for about one third of all feline pruritic cases [3]. C. Noli (*) Servizi Dermatologici Veterinari, Peveragno, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_20 437 VetBooks.ir 438 C. Noli Fig. 1 Microscopic aspect of the cat flea Ctenocephalides felis felis (4×) Pathogenesis of Flea Allergy Cats are bitten by fleas several times a day [4]. Fleas insert their mouthparts through the epidermis in the dermis and suck blood from the capillaries. During this procedure, they deposit up to 15 salivary proteins within the epidermis and superficial dermis that soften tissues and prevent blood coagulation [5, 6]. Hypersensitivity to these proteins induces local edema and a cellular infiltrate, which constitutes the erythematous papule that may follow the bite. There are no specific studies yet that identify the precise allergenic components of flea saliva relevant for naturally sensitized cats. One study suggests that FSA1 (feline salivary antigen-1) may be a major flea saliva antigen in experimentally sensitized laboratory cats [7]. It is thought that non-allergic animals suffer little or no discomfort while being bitten and that only flea allergic subjects develop pruritus and skin disease. Little is known about the pathogenesis of flea allergy in cats. Most flea allergic cats have immediate positive intradermal skin test reactions to flea allergens and delayed, type 4 reactions have been also described [8, 9]. As in dogs, allergen- specific IgE can be found in the serum of flea allergic cats by means of ELISA [8, 10]. Late-phase IgE-mediated cellular response and cutaneous basophil hypersensitivity have not yet been identified in cats. Results of a study on early sensitization of 12-week-old kittens, which developed only mild clinical signs (10/18 kittens), suggest that cats exposed to fleas early in their life are less likely to develop flea allergy than cats exposed at a later age [11]. The authors suggested that early ingestion of fleas could induce tolerance, as cats experimentally exposed to fleas orally tended to have minimal clinical VetBooks.ir Flea Biology, Allergy and Control 439 signs and lower in vivo and in vitro test scores, although this was not statistically different from the controls [11]. In the same study, cats continuously exposed to fleas from 16 to 43 weeks of age developed either immediate or late reactivity to live flea challenge. However, the same cats were not all positive on intradermal or serology testing. Immediate test reactivity was reported to persist for more than 90 days after experimental sensitization [7]. In a study specifically designed to clarify the role of intermittent exposure to flea bites, it was concluded that it had neither a protective nor a predisposing effect on the development of clinical signs of flea allergy [12]. Clinical Appearance There is no age, breed, or sex predilection for the development of flea-bite hypersensitivity. In most cases flea control is either completely lacking or incomplete or wrongly performed. Clinical signs are usually worse in the warmer months, particularly at the end of the summer, when the flea population is at its highest point. In addition, many owners stop administering flea control in the same period, as they feel it is no longer needed. Clinical signs of feline flea allergy are not different from those caused by other allergies in cats and include, alone (75% of cats) or in combination, pruritus, miliary dermatitis, self-induced alopecia, eosinophilic plaque and eosinophilic granuloma, lip ulcer and head and neck excoriations [3]. Please refer to Chapter, Feline Atopic Syndrome: Epidemiology and Clinical Presentation for a more extensive description of these clinical presentations. All of these signs could be reproduced in experimental sensitization studies [12]. Prevalence of lesions in flea-bite allergy is detailed in Table 1 [3]. A multicentric study on 502 pruritic cats reported a preferred localization of pruritus and lesions of miliary dermatitis on the caudal dorsum (Fig. 2) in cats with flea-bite hypersensitivity, if compared with other allergies [3]. In the same study, non-dermatological signs, such as conjunctivitis, rhinitis, vomiting, diarrhea, and soft feces, were observed in 30% of cats with flea-bite allergy, and otitis was observed in 3% [3]. Table 1 Prevalence of clinical sign of allergy in cats with flea bite hypersensitivity (reference Hobi) Clinical sign Miliary dermatitis Prevalence 35% Symmetrical alopecia 39% Head and neck pruritus and excoriations Eosinophilic granuloma complex (including eosinophilic granuloma, eosinophilic plaque and lip ulceration) 38% 14% Most frequent distribution Caudal dorsum, caudal thighs or generalized Caudal dorsum and flank Abdomen Head and neck Granuloma: mouth, chin, caudal aspect of the hind legs Plaque: abdomen, groin Lip ulcer: upper lips VetBooks.ir 440 C. Noli Fig. 2 Self-inflicted lesions on the back of a cat with flea-bite allergy Fig. 3 Fleas and flea feces found in the coat of a non-allergic cat Differential Diagnoses and Diagnostic Approach A dermatological examination of a cat should always include search for fleas and their feces, by means of a thorough fine-tooth combing of the whole patient (Figs. 3, 4 and 5). Flea feces are made of dry blood and can be easily recognized as they will leave a brown halo on a white moistened paper towel. Fleas or flea feces are not always found as cats are excellent groomers and can eliminate all fleas in a few hours [13]. Furthermore, the number of eggs that fall off flea allergic cats in the environment is lower, leading to a less obvious animal and environmental infestation [13]. For this reason, a lack of fleas or flea dirt in the coat does not exclude a diagnosis of flea allergy. The main differential diagnoses of flea allergy are other allergies, such as adverse reactions to food and environmental allergic dermatitis, VetBooks.ir Flea Biology, Allergy and Control 441 Fig. 4 Abundant flea feces and some adult fleas obtained by flea combing in a flea-infested cat Fig. 5 Microscopic aspect of the same material of Fig. 4: flea feces appear as red, curled structures. They are made by over 90% of the cat’s dry blood. This is an important parental investment by the female flea, as flea feces represent the main nourishment for the flea larvae because they share all the abovementioned clinical manifestations. Other less frequent differentials are other parasitic diseases (Chapter, Ectoparasitic Diseases), psychogenic alopecia (Chapter, Psychogenic Diseases), dermatophytosis (for miliary dermatitis) and rare, pruritic, immune-mediated, autoimmune and neoplastic diseases. A suspect diagnosis of flea allergy may be confirmed by performing an intradermal skin test. The flea allergen is injected (0.05 ml) intradermally together with a negative (saline) and a positive (histamine) control and reactions are read at 15 minutes and 48 hours. Current or recent administration of glucocorticoids or antihistamines (2 weeks for short-acting glucocorticoids and antihistamines, up to 8 weeks for depot glucocorticoids) may cause false-negative results. False-positive VetBooks.ir 442 C. Noli reactions in normal cats have been described: in one study, 36% of clinically normal cats that had been exposed to fleas had a positive immediate skin test reaction to flea antigens [14]. A positive predictive value of 85–100% was reported in earlier studies [9, 12, 15], while a more recent study performed with three different extracts obtained a sensitivity of 33% and a specificity of 78–100% [8]. In a study on experimental induction of flea hypersensitivity, the presence of positive immediate intradermal test reactions did not correlate with the development of clinical signs [11]. Allergens used in older studies were whole body flea extracts (1:1000 w/v), while more recently flea saliva or purified salivary antigens have been developed for a more sensitive in vivo test [5]. However, in experimentally induced feline flea-bite allergy, results of intradermal testing with purified allergens were not superior to crude extracts in the correlation with clinical signs [11, 12]. Furthermore, it is not known if the concentration used (1/1000 w/v) extrapolated from dogs is optimal for cats or if higher concentrations should be used [16]. In vitro serologic tests (ELISA) with whole body flea extracts or purified flea saliva or recombinant flea saliva antigens are available for determination of allergen- specific IgE in the feline serum. The readers should be warned that these tests may only identify animals with IgE-mediated disease and fail to diagnose those with a delayed reaction only. Furthermore, there are normal cats which may have allergen- specific IgE in the absence of clinical disease [8, 11, 12]. Sensitivity and specificity of serological tests performed with flea extracts were reported to be 88% and 77%, respectively, in one study [8] and 77% and 72% in another study [15], with a low positive predictive value of 0.58 in the latter one. Flea saliva represents only 0.5% of whole flea extracts and in vitro tests performed in dogs with flea salivary antigens gave much better results than those performed with whole flea extracts [17]. In vitro test with salivary antigens and the use of high-affinity receptors FcεR1α gave an overall accuracy of 82% and may represent a more reliable tool for the diagnosis of flea allergy in cats [Mc Call]. In practice, the best approach to the correct diagnosis is to implement an effective ectoparasite control together with/followed by a good hypoallergenic diet. If an improvement is obtained, a dietary challenge can differentiate between flea-bite allergy and food hypersensitivity. If no improvement is obtained, then environmental allergy or other less frequent pruritic conditions can be taken into consideration (Chapter, Feline Atopic Syndrome: Diagnosis for a detailed description of the diagnostic approach to the pruritic cat). Treatment Flea control is pivotal for an effective treatment of flea-bite allergy. Adult fleas are obligate ectoparasites [4] and topical or systemic flea control on the cat is mandatory. However, the development of the life stages from egg through to pupa occurs in the immediate domestic environment of the infested pet rather than on the host and this requires adjunct environmental treatment [1, 4, 18]. Contact with other VetBooks.ir Flea Biology, Allergy and Control 443 cats is another source of infection. Unfortunately, in a survey conducted on owners of flea-infested animals, only 71% of dogs and 50% of cats had been treated against fleas in the previous 12 months [19]. One of the most frequent challenges of treating fleas is that many owners, particularly in case of absence of parasites and feces on the cat’s coat, will be skeptical and feel offended if faced with the assumption that there could be fleas on their pets and in their homes and will thus be unwilling to perform a thorough flea control. Explaining that there is no need to host high amounts of fleas to develop allergy and that only a well-conducted all-year-round flea control is able to prevent flea infestation can increase owner compliance. The Flea Cycle and Ecology Veterinarians should take time to thoroughly explain why and how to perform correct flea control. This begins with telling the owner something about the flea cycle [1, 4]. Flea eggs are produced on the host and fall off within 8 hours of production. High egg counts have been found in places where the animal sleeps, eats, or spends most of its time. The eggs hatch after 1–10 days (Fig. 6). The larvae live freely in the environment and move actively under furniture and rugs, deep in carpet fibers, or under organic debris (grass, branches, leaves), in order to avoid light. After 5–11 days, the larvae produce a silk-like cocoon for their protection and camouflage. Inside the cocoon the larvae develop into pupae and then in 5–9 days become young adults. The fleas in the cocoon are very well protected from insecticides and unfavorable environmental conditions and may survive in a quiescent state for up to 50 weeks. If a potential host is there, the fleas exit the cocoon and rapidly jump on it. If no host is available, the newly emerged fleas can survive several days (up to a b Fig. 6 Flea feces, eggs, and larvae obtained from the environment (couch) of a flea-infested cat. (4×) VetBooks.ir 444 C. Noli 2 weeks) in the environment. If the fleas do not find a domestic animal, they often bite humans before finding their preferred host. Adult fleas are permanent parasites of animals. As soon as they land on a host, they begin to feed. The first eggs are produced on the host after 36–48 hours. One single female is capable of producing up to 40–50 eggs a day and up to 2000 eggs in about 100 days of life. The minimum length of the whole cycle is 12–14 days, with an average of about 3–4 weeks in most household conditions, in winter as well. Adult fleas account for only 1–5% of all fleas in the cat’s environment, 95–99% of the fleas being the egg, larval, or pupal stage. In fact, it is thought that in temperate climates, the house is the major source of re-infestation of small animals. Flea Control Factors important for successful flea control are efficacy and safety of the active ingredient, possibly with long residual activity. Molecules effective on fleas usually belong to one of two categories: either they kill adult fleas (adulticides) or they inhibit pre-adult stage development (insect growth regulators). Adulticides are needed on the animal, in order to kill adult fleas on the host, ideally before they bite and elicit the allergic reaction. Adulticides alone kill only 1–5% of the flea population and do not stop environmental (household) infestation, i.e., eggs, larvae and pupae, representing 95–99% of the entire flea population. Insect growth regulators are able to inhibit development of eggs and larvae and decrease environmental infestation, but cannot prevent the allergic animal from being bitten by an adult flea which comes from “outside” the house. Therefore both product types are needed together for effective flea control, especially for flea allergic animals, in order to break the flea life cycle in at least two stages. A list of antiparasitic products available on the market for cats, with their characteristics, is provided in Table 2. Published trials on flea control measures have been recently extensively reviewed by Rust [1]. The best way to quickly and surely eliminate infestation in a cat is by administering an oral parasiticide. Nitenpyram is the most rapid one, as its effect is seen as soon as 15–30 minutes after administration [20]. Nitenpyram is thus an excellent means of diagnosing the presence of fleas, if given as soon as the cat enters the clinic, as fleas can be seen falling on the table during the consultation. However, being its duration of effect so short (48 hours in cats), it is not very practical as a flea prevention means (the drug should be administered every 48–72 hours). Other oral flea control products, with a slower onset of efficacy (8–12 hours) but with the advantage of a monthly duration, are spinosad and lotilaner [21, 22]. In one study, oral products were considered more effective than topical spot-ons applied by the owner in dogs [23], probably due to better reliability of the mode of administration. There is no data on cats. Other common flea control measures are spot-on formulations containing an adulticide (imidacloprid, fipronil, selamectin, metaflumizone, dinotefuran, indoxacarb) Flea Biology, Allergy and Control 445 VetBooks.ir Table 2 Antiparasitic products available on the market for cats against fleas, at the time of writing Name original Active ingredient producta Frontline Fipronil Formulationb Spot-on Minimum age of use 8 weeks Fipronil Methoprene Fipronil Pyriproxyfen Fipronil Methoprene Eprinomectin Praziquantel Spot-on 8 weeks Spot-on 10 weeks Spot-on 7 weeks Advantage Advocate Imidacloprid Imidacloprid Moxidectin Spot-on Spot-on 8 weeks 9 weeks Stronghold/ Revolution Selamectin Spot-on 6 weeks Stronghold plus Selamectin Sarolaner Spot-on 8 weeks Comfortis Spinosad 14 weeks Activyl Vectra felis 8 weeks 7 weeks Fleas Fleas No Yes Bravecto Indoxacarb Dinotefuran Pyriproxyfen Fluralaner Tablets (with food!) Spot-on Spot-on Parasitesc Fleas, ticks, lice, Cheyletiella Fleas, ticks, lice, Cheyletiella Fleas, ticks, lice, Cheyletiella Fleas, lice, Otodectes, Demodex, heartworm, Notoedres, Cheyletiella, Angiostrongylus, GE nematodes, tapeworm Fleas Fleas, lice, Otodectes, Demodex, heartworm, Notoedres, Cheyletiella, GE nematodes Fleas, lice, Otodectes, Demodex, heartworm, Notoedres, Cheyletiella, GE nematodes Fleas, ticks, lice, Otodectes, Demodex, Cheyletiella, Notoedres, heartworm, myiasis, GE nematodes Fleas, myiasis Spot-on (12 weeks) 8 weeks No Bravecto plus Fluralaner Moxidectin Spot-on (12 weeks) 9 weeks Credelio Lotilaner Tablet (with food!) 8 weeks Seresto/ Foresto Imidacloprid Flumethrin Collar (6–8 months) 10 weeks Fleas, lice, ticks, Otodectes, Demodex, Notoedres, Cheyletiella, myiasis Fleas, ticks, lice, Otodectes, Demodex, Cheyletiella, Notoedres, heartworm (8 weeks), GE nematodes, myiasis Fleas, ticks, lice, Otodectes, Demodex, Cheyletiella, Notoedres, myiasis Fleas, ticks, sandflies, mosquitoes Frontline combo Effipro Duo Broadline IGR effect No Yes Yes Yes Yes Yes Yes Yes No No No Yes (continued) 446 C. Noli VetBooks.ir Table 2 (continued) Name original Active ingredient producta Capstar Nitenpyram Formulationb Tablet (activity 72 h) Minimum age of use 4 weeks Parasitesc Fleas, myiasis IGR effect No The original/first product marketed with this ingredient is reported in the table. Depending on the country, several other products are currently available containing fipronil, fipronil/methoprene, fipronil/pyriproxyfen, and imidacloprid b Monthly administration unless stated otherwise c Both label and “off-label” parasites are reported in this table a to be administered between the shoulder blades every 4 weeks. Pulicidal efficacy of each one of these drugs has been proven to be excellent (at least 90%) for up to 4 weeks in laboratory clinical trials [1]. Among these, indoxacarb is a pro-insecticide that must be bio-activated by insect enzymes to generate the active metabolite able to kill fleas and ticks. In mammals, indoxacarb is metabolized to inactive molecules by the liver and is not toxic, so that it is designated by the US Environmental Protection Agency as a “reduced risk” pesticide. Recently, a new spot-on formulation for cats based on fluralaner, a member of a new class of antiparasitic agents, the isoxazolines, has been marketed with a residual activity against fleas for up to 3 months [24]. Fluralaner is absorbed transdermally and redistributed systemically, so that fleas will need to bite the cat to be killed. A 3-month duration time probably improves owner’s compliance and can be preferred in allergic subjects. There is one flea collar registered for use in the cat containing 10% imidacloprid and 4.5% flumethrin, with a 6–8-month-long pulicidal activity. This product has the advantages of being less expensive than spot-ons or tablets, with a higher compliance and repellent efficacy against fleas, ticks, mosquitos and sandflies vectors of leishmaniosis [25]. Some of the abovementioned insecticides also offer ovicidal and larvicidal activity (e.g., imidacloprid [26] or selamectin [27]), while others are formulated in association with an IGR, such as pyriproxyfen or methoprene. Insect growth regulators (IGR) interfere with the development of pre-adult flea stages, which account for the vast majority of the total flea population (up to 99%). They have a very low toxicity for mammals, because they act on very insect-specific metabolic pathways. The idea behind administering a product with IGR effect on the animal is that treated hairs shed in the environment are able to inhibit eggs’ hatching and/or larval moulting. The use of an IGR is fundamental to reduce the environmental flea population, thus the flea burden on the cat and the consequent clinical symptomatology. IGR sprays, containing methoprene or pyriproxyfen, can also be used in the e nvironment, especially in case of heavy or recurrent infestation. The principal strategic problem in trying to control a domestic flea population, however, is dealing with young adult fleas within the protective pupal case [23]. These can yield live, viable adults for periods of several months after all eggs, larvae and other adults have been killed, and repeated applications of environmental treatment may be necessary in some cases. Recently a 0.4% environmental dimeticone spray was able to VetBooks.ir Flea Biology, Allergy and Control 447 prevent emergence of young adult fleas from cocoons and proved to be efficacious in immobilizing larvae and adults in the environment [28], with efficacy persisting for more than 3 weeks. Certain physical measures can assist in flea control. Washable surfaces can be cleaned to remove organic matter and flea feces on which larvae feed. Vacuum cleaning will remove 20% of larvae and up to 60% of eggs as well as flea feces and organic matter. Vacuum cleaning assists spray penetration by raising the fibers in carpets. Bedding and other washable items should be laundered at the highest temperature possible. Carpets and soft furnishings should not be washed as increased humidity favors larval development. How to Perform an Effective Flea Control and Causes of Failure An adulticide has to be applied to every animal in the household all year round and an IGR has either to be applied in the environment or to all pets. Flea control must be thoroughly and constantly applied in order to be effective; thus, client compliance is the most important element for a successful flea control. Recurrence of signs usually depend on lack in flea control, which might be due to one or more of these factors [29]: –– –– –– –– Use of ineffective products Insufficient dosage or lack of application in the whole house or on all animals Use of adulticides without IGR or IGR without adulticides Too long period of time between administrations Questioning the owner about how they perform flea control will nearly always identify the problem and it is our task to explain and convince them about the importance of a complete flea control. Although flea control is mandatory, it may not be sufficient to result in complete control of the dermatosis in all cases, particularly where there is continued contact with untreated individuals. In such cases, anti-pruritic treatment will be necessary. Please refer to Chapter, Feline Atopic Syndrome: Therapy for a detailed discussion of anti-pruritic drugs in cats. The potential for vaccination, either against the immunogenic salivary proteins of the flea or against concealed antigens within the flea gut, has been explored with variable results and could offer possibilities for the future management of flea allergy [7, 30–32]. Conclusion Flea-bite hypersensitivity is one of the most important allergic skin conditions in cats, which can manifest with different clinical signs and has many possible differential diagnoses. Intradermal and in vitro allergy tests are not always reliable diagnostic tools and rigorous flea control, by means of adulticides and insect growth regulators, represents the best tool for diagnosing and treating this condition. 448 C. Noli VetBooks.ir References 1. Rust MK. The biology and ecology of cat fleas and advancements in their Pest management: a review. Insects. 2017;8:118. 2. Shaw SE, Birtles RJ, Day MJ. Arthropod transmitted infectious diseases of cats. J Feline Med Surg. 2001;3:193–209. 3. Hobi S, Linek M, Marignac G, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 4. Dryden MW, Rust MK. The cat flea: biology, ecology and control. Vet Parasitol. 1994;52:1–19. 5. Frank GR, Hunter SW, Stiegler GL, et al. Salivary allergens of Ctenocephalides felis: collection, purification and evaluation by intradermal skin testing in dogs. In: Kwochka KW, Willemse T, von Tscharner C, editors. Advances in veterinary dermatology, volume 3. Oxford: Butterworth Heinemann; 1998. p. 201–12. 6. Lee SE, Johnstone IP, Lee RP, et al. Putative salivary allergens of the cat flea, Ctenocephalides felis felis. Vet Immunol Immunopathol. 1999;69:229–37. 7. Jin J, Ding Z, Meng F, et al. An immunotherapeutic treatment against flea allergy dermatitis in cats by co-immunization of DNA and protein vaccines. Vaccine. 2010;28:1997–2004. 8. Bond R, Hutchinson MJ, Loeffler A. Serological, intradermal and live flea challenge tests in the assessment of hypersensitivity to flea antigens in cats (Felis domesticus). Parasitol Res. 2006;99:392–7. 9. Lewis DT, Ginn PE, Kunkle GA. Clinical and histological evaluation of immediate and delayed flea antigen intradermal skin test and flea bite sites in normal and flea allergic cats. Vet Dermatol. 1999;10:29–38. 10. McCall CA, Stedman KE, Bevier DE, Kunkle GA, Foil CS, Foil LD. Correlation of feline IgE, determined by Fcε RIα-based ELISA technology, and IDST to Ctenocephalides felis salivary antigens in a feline model of flea bite allergic dermatitis. Compend Contin Educ Pract Vet. 1997;19(Suppl. 1):29–32. 11. Kunkle GA, McCall CA, Stedman KE, Pilny A, Nicklin C, Logas DB. Pilot study to assess the effects of early flea exposure on the development of flea hypersensitivity in cats. J Feline Med Surg. 2003;5:287–94. 12. Colombini S, Hodgin EC, Foil CS, Hosgood G, Foil LD. Induction of feline flea allergy dermatitis and the incidence and histopathological characteristics of concurrent indolent lip ulcers. Vet Dermatol. 2001;12:155–61. 13. McDonald BJ, Foil CS, Foil LD. An investigation on the influence of feline flea allergy on the fecundity of the cat flea. Vet Dermatol. 1998;9:75–9. 14. Moriello KA, McMurdy MA. The prevalence of positive intradermal skin test reactions to lea extracts in clinically normal cats. Comp Anim Pract. 1989;19:28–30. 15. Foster AP, O’Dair H. Allergy skin testing for skin disease in the cat in vivo vs in vitro tests. Vet Dermatol. 1993;4:111–5. 16. Austel M, Hensel P, Jackson D, et al. Evaluation of three different histamine concentrations in intradermal testing of normal cats and attempted determination of the irritant threshold concentrations of 48 allergens. Vet Dermatol. 2006;17:189–94. 17. Cook CA, Stedman KE, Frank GR, Wassom DL. The in vitro diagnosis of flea bite hypersensitivity: flea saliva vs. whole flea extracts. In: Proceedings of the 3rd veterinary dermatology world congress, 1996 Spet 11–14. Edinburgh; 1996. p. 170. 18. Osbrink WLA, Rust MK, Reierson DA. Distribution and control of cat fleas in homes in Southern California (Siphonaptera: Pulicidae). J Med Entomol. 1986;79:135–40. 19. Peribáñez MÁ, Calvete C, Gracia MJ. Preferences of pet owners in regard to the use of insecticides for flea control. J Med Entomol. 2018;55:1254–63. 20. Dobson P, Tinembart O, Fisch RD, Junquera P. Efficacy of nitenpyram as a systemic flea adulticide in dogs and cats. Vet Rec. 2000;147:709–13. VetBooks.ir Flea Biology, Allergy and Control 449 21. Cavalleri D, Murphy M, Seewald W, Nanchen S. A randomized, controlled field study to assess the efficacy and safety of lotilaner (Credelio™) in controlling fleas in client-owned cats in Europe. Parasit Vectors. 2018;11:410. 22. Paarlberg TE, Wiseman S, Trout CM, et al. Safety and efficacy of spinosad chewable tablets for treatment of flea infestations of cats. J Am Vet Med Assoc. 2013;242:1092–8. 23. Dryden MW, Ryan WG, Bell M, et al. Assessment of owner-administered monthly treatments with oral spinosad or topical spot-on fipronil/(S)-methoprene in controlling fleas and associated pruritus in dogs. Vet Parasitol. 2013;191:340–6. 24. Bosco A, Leone F, Vascone R, et al. Efficacy of fluralaner spot-on solution for the treatment of ctenocephalides felis and otodectes cynotis mixed infestation in naturally infested cats. BMC Vet Res. 2019;15:28. 25. Brianti E, Falsone L, Napoli E, et al. Prevention of feline leishmaniosis with an imidacloprid 10%/flumethrin 4.5% polymer matrix collar. Parasit Vectors. 2017;10:334. 26. Jacobs DE, Hutchinson MJ, Stanneck D, Mencke N. Accumulation and persistence of flea larvicidal activity in the immediate environment of cats treated with imidacloprid. Med Vet Entomol. 2001;15:342–5. 27. McTier TL, Shanks DJ, Jernigan AD, Rowan TG, Jones RL, Murphy MG, et al. Evaluation of the effects of selamectin against adult and immature stages of fleas (Ctenocephalides felis felis) on dogs and cats. Vet Parasitol. 2000;91:201–12. 28. Jones IM, Brunton ER, Burgess IF. 0.4% dimeticone spray, a novel physically acting household treatment for control of cat fleas. Vet Parasitol. 2014;199:99–106. 29. Halos L, Beugnet F, Cardoso L, et al. Flea control failure? Myths and realities. Trends Parasitol. 2014;30:228–33. 30. Heath AW, Arfsten A, Yamanaka M, et al. Vaccination against the cat flea Ctenocephalides felis felis. Parasite Immunol. 1994;16:187–91. 31. Halliwell REW. Clinical and immunological response to alum-precipitated flea antigen in immunotherapy of flea-allergic dogs: results of a double blind study. In: Ihrke PJ, Mason IS, White SD, editors. Advances in veterinary dermatology, vol. 2. Oxford: Pergamon Press; 1993. p. 41–50. 32. Kunkle GA, Milcarsky J. Double-blind flea hyposensitization trial in cats. J Am Vet Med Assoc. 1985;186:677–80. VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation Alison Diesel Abstract Although very well defined and characterized in the dog, feline atopic syndrome remains less well understood with regard to disease pathogenesis and clinical presentations. While many similarities exist, questions remain whether atopic dermatitis is the same disease entity in dogs and cats. Atopic dermatitis in the cat is often referred to as “feline atopic syndrome” or “non-flea, non-food hypersensitivity dermatitis (NFNFHD).” Although the diagnostic process is similar for dogs and cats, with both being a diagnosis of exclusion, demonstration of immunoglobulin-E (IgE) involvement in feline atopic syndrome has been inconclusive. As with canine atopic dermatitis, pruritus remains a feature of the disease in cats; however, the distribution of pattern of pruritus and lesions is more variable in feline patients. Cats with feline atopic syndrome will typically present with at least one of four common cutaneous reaction patterns (head/neck/pinnal pruritus with excoriations, self-induced alopecia, miliary dermatitis, eosinophilic skin lesions). Additionally, non-cutaneous clinical signs may also be observed. Introduction Although very well defined and characterized in dogs and humans, feline atopic syndrome remains less well understood with regard to disease pathogenesis and clinical presentations. While many similarities exist, questions remain whether atopic dermatitis is the same disease entity in dogs and cats. In general, when allergic skin disease is compared across the two species, much less is known/documented A. Diesel (*) College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA e-mail: ADiesel@cvm.tamu.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_21 451 VetBooks.ir 452 A. Diesel in cats, especially in regard to atopic dermatitis. While the term “feline atopy” has been a part of the veterinary literature since 1982 [1], this terminology has fallen out of favor when discussing the disease in cats. “Feline atopic dermatitis” was used initially to describe a clinical syndrome in feline patients with recurrent pruritic skin disease, positive reactions to several environmental allergens on intradermal testing and where other causes of pruritus (e.g., external parasites, infections) had been ruled out. Due to the lack of conclusive demonstration of immunoglobulin-E (IgE) involvement in the disease process, most veterinary dermatologists prefer either “feline atopic syndrome” (FAS) or “non-flea, non-food hypersensitivity dermatitis” (NFNFHD) when referring to what was historically referred to as feline atopic dermatitis (AD) [2]. While the condition remains a diagnosis of exclusion in both species, feline atopic syndrome presents a unique set of challenges for the veterinary practitioner. This includes not only quandaries in interpretation of diagnostic tests but also evaluation of the particular clinical syndromes unique to the feline patient and currently limited options for therapeutic intervention compared to the canine counterpart. This chapter aims to discuss what is presently known with regard to the pathogenesis of feline atopic syndrome, the epidemiology of disease, and observed clinical presentations. Subsequent chapters will present a discussion on diagnostic evaluations and current therapy. Pathogenesis of Feline Atopic Syndrome Compared to dogs and people where the pathogenesis of atopic dermatitis is relatively well characterized [3–5], there remains a paucity of information present in the literature with regard to the development of feline atopic syndrome. Although the body of information continues to grow in certain areas of disease pathogenesis for dogs and people (particularly in regard to influences in barrier function and more specific immunological factors), many of these foci have not yet been explored for the allergic feline patient. What has been documented, however, can be discussed with regard to the historical classic triad of factors involved in the development of atopic dermatitis (genetic influence, environmental factors, immunological abnormalities) and influences of barrier function on the course of disease. Genetic Factors In dogs and people, it is relatively well established that a genetic predisposition will often contribute to an allergic phenotype, specifically in relation to the development of atopic dermatitis. This has been shown in several human twin studies [6] and in the evaluation of the influence of filaggrin mutation as a contributory factor [7]. In the dog, specific phenotypes have been described for several commonly affected canine breeds [8]; however as in people, it is clear genetics is only part of the picture. The complex genotype of canine atopic dermatitis, with multiple genes VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation 453 involved in the genetic component of the disease development, indeed speaks of the multifaceted nature of the disease. That said, with certain documented genetic variations and improved understanding of the genetic influence for certain patients, targeted therapy aimed at specific molecules may be able to be developed and implemented in the future [9]. In the cat, however, genetic influence in the development of feline atopic syndrome has been only loosely documented [10]. While it seems plausible that indeed there is a genetic component to the disease in cats, to what degree this is apparent is far from known at this time. Environmental Factors As is seen with atopic dermatitis in dogs and people, exposure to environmental allergens exacerbates clinical signs in cats with atopic syndrome [11]. This is apparent in the naturally occurring disease presentation and has been supported with a clinical model. In a study utilizing a modified patch test with aeroallergens applied to the skin of healthy and allergic cats, only cats with atopic syndrome developed an inflammatory infiltrate similar to that seen in the lesional skin of cats with the spontaneous disease [12]. Whether application or exposure to aeroallergens in a laboratory setting would lead to more generalized lesions associated with atopic syndrome in the cat, as it does in dogs [13], has not been investigated. Although a positive “allergy test” does not diagnose atopic dermatitis in any known species, the historical definition of atopic dermatitis in the cat [1] included the description of cats with several positive reactions to environmental allergens on intradermal allergen tests. Intradermal allergen testing (as well as serum allergen testing) for environmental allergens remains a cornerstone of support for the clinical diagnosis of feline atopic syndrome (see further discussion in Chapter, Feline Atopic Syndrome: Diagnosis). This combined with a favorable response to allergen immunotherapy in many cats with atopic syndrome further supports the influence of environmental factors in disease pathogenesis. Immunological Findings in Cats with Atopic Syndrome Pulling together all aspects of the disease, the current definition of canine atopic dermatitis describes “a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with IgE antibodies most commonly directed against environmental allergens” [14]. The influence of IgE has clearly been demonstrated in this species as well as in people; however, this association is less well defined for feline atopic syndrome. Indeed, the role of IgE remains an area of contention with regard to the immunological factors lending to disease development. Part of the argument stems from a lack of correlation with serum IgE levels in cats and clinical disease [15]; however, levels of allergen-specific IgE do not always correlate with clinical disease in canine atopic dermatitis either [16]. VetBooks.ir 454 A. Diesel There is a reasonable body of evidence, however, that supports the influence of IgE in hypersensitivity dermatitis in the cat. Passive cutaneous anaphylaxis testing has been used in cats to demonstrate the transfer of allergen-specific cutaneous reactivity from a sensitized/allergic cat to a naïve feline via injection of serum from the allergic individual [17, 18]. This reactivity, however, does not occur if the serum is heated prior to injection. The heating process inactivates IgE but not other antibodies, thereby supporting IgE involvement [17, 19, 20]. When anti-IgE is injected into the skin of normal cats, immediate and delayed inflammatory responses occur [21], sharing many macroscopic and microscopic features of what has previously been reported in cats with spontaneously occurring allergic skin disease [10, 15]. A similar inflammatory response, however, was not observed with injection of IgG in this group [21], again supporting the involvement of IgE in feline hypersensitivity dermatitis. The role of IgE has been well established in other allergic diseases in the cat, most notably feline asthma [20, 22]. Given this condition occurs not infrequently in cats with (presumed) allergic skin disease [23], the suspected role of IgE in the phenotype of both conditions cannot be ignored. Although there is still a bit of uncertainty in regard to the immunopathogenesis of feline atopic syndrome, there is a similar pattern of inflammatory infiltrate in the skin of allergic cats compared to that which is seen in humans and dogs with chronic atopic dermatitis [24]. Certain cell types involved in the innate and adaptive immune system can be seen in altered numbers in the skin of allergic cats compared to those without hypersensitivity dermatitis. Dendritic cells, including Langerhans cells, have been reported in higher numbers in allergic feline skin [24, 25]. These cells interface with the environment, lending to development of allergic inflammation, and have been implicated as well in the generation of atopic dermatitis in people [26]. Eosinophils, often seen with various allergic diseases across multiple species, are additionally increased in the skin of cats with allergy. Indeed, these cells are a conspicuous infiltrate in inflammatory lesions of feline allergic dermatitis, particularly in miliary dermatitis lesions, and are suspected to be the more specific indicator of a hypersensitivity response in cutaneous allergy in cats [27]. Tissue inflammation occurs secondary to the release of granule contents, including major basic protein, as well as inflammatory cytokine expression [28]. Although not specific to hypersensitivity dermatitis in the cat, mast cells are often increased in the skin of cats with allergies compared to healthy cat skin [27]. Additionally, as is seen in people with atopic dermatitis [29], mast cells in allergic cat skin undergo a change in granule content. In cats with allergic skin disease, a markedly lower number of mast cells have been observed staining for tryptase as opposed to chymase [27]. This is compared to healthy cat skin where all mast cells can be seen with tryptase staining and approximately 90% observed when staining for chymase [30]. It has been well documented that a skewed T-cell response in favor of T helper 2 (Th2) over Th1 is a part of the immunological development of atopic dermatitis in dogs and people. T cell involvement also appears to be involved in the immunopathogenesis of feline atopic syndrome. This has been seen with histopathological studies documenting increased populations of CD4+ T cells in allergic cat skin compared to that of CD8+; these cells are generally not observed in the skin from healthy cats [31]. Additionally, an increased number of IL-4 producing T cells have VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation 455 been found in the skin of allergic cats compared to that of healthy controls, supportive of a Th2 infiltrate [32]. This skewed population of T cells has not, however, been demonstrated in the peripheral blood of allergic cats compared to healthy controls [31]. The inflammatory cytokine profile has also not been well elucidated in the skin or peripheral blood of cats with feline atopic syndrome. Differences in the gene expression of various inflammatory interleukins and other cytokines could not be detected when comparing the skin of normal, lesional, and non-lesional allergic cat skin [33]. More recently, increased circulating levels of IL-31 have been demonstrated in sera from allergic cats compared to those without allergic skin disease [34] as has been shown in canine atopic dermatitis. This suggests involvement of this inflammatory cytokine in feline allergic dermatoses; however, a causative role has yet to be determined. Skin Barrier and Other Factors The role of barrier function in the skin of people and dogs with atopic dermatitis has become an increasingly important area of investigation. This factor, however, has not been well explored in cats with feline atopic syndrome. One study observed differences in transepidermal water loss (TEWL), skin hydration, and pH at various body sites in healthy cats [35]. Recently, a study examined the relationship between TEWL and severity of clinical symptoms in cats with feline atopic syndrome [36]. Using two scoring systems to assess skin lesions in allergic cats (Scoring Feline Allergic Dermatitis (SCORFAD) and Feline Extent and Severity Index (FeDESI)), a positive correlation was observed between TEWL and severity of clinical lesions at certain body sites, particularly when using the SCORFAD measurements. Less association was observed with FeDESI scoring. While there may indeed be differences in TEWL in allergic cats compared to healthy controls, the measurements may be less useful compared to what is seen in dogs and humans with atopic dermatitis. In people and dogs with atopic dermatitis, bacterial infection and yeast overgrowth can exacerbate clinical signs of disease. The same appears to be true in some cats with feline atopic syndrome; secondary infections, however, with either bacteria or yeast tend to occur less frequently in allergic cats compared to allergic dogs or people. Although the exact implications have yet to be determined, there is a growing body of evidence documenting changes in the microbiome in atopic individuals. Indeed, this has been reported in both humans [37] and dogs [38], and more recently in allergic cats compared to healthy controls [39]. While there are some similarities across species (e.g., the Staphylococcus species is more abundant in allergic individuals compared to healthy controls), there are additionally species differences. Contrary to allergic dogs and humans, allergic cats seem to retain microbial diversity, in that the number of bacterial species was not significantly different in allergic compared to healthy individuals [39]. Furthermore, compared to dogs and people where differences in bacterial communities are seen at specific body locations in the face of an allergic “flare,” in allergic cats, their entire body becomes colonized by an altered bacterial population independent of location sampled. This is postulated to be due to the fastidious grooming behavior of cats. VetBooks.ir 456 A. Diesel These differences may partially explain why secondary infections are less common in allergic cats compared to what is observed in dogs in people. What implication this dysbiosis has in disease development and/or response to therapeutic intervention remains yet to be discovered. Epidemiology of Feline Atopic Syndrome The exact prevalence of feline atopic syndrome in the general population has not been well described in the veterinary literature. A retrospective study on the population of cats seen at a teaching hospital in the United States identified “allergies” accounting for 32.7% of the feline skin diseases presented to the hospital during a 15-year period. “Atopic dermatitis” itself represented 10.3% of the feline dermatoses observed [40]. A similar study over a 1-year period at a university teaching hospital in Canada diagnosed “atopic dermatitis” in 7 of 111 (6.3%) presented for evaluation of dermatological disease [41]. In another study evaluating dermatological diseases seen in general practice in the United Kingdom, however, only 2 out of 154 (1.3%) cats were diagnosed with “atopic dermatitis.” It is important to note, however, that other cutaneous reaction patterns (e.g., miliary dermatitis, eosinophilic granuloma complex) were observed in this population without a defined etiology [42]. This difference of prevalence may also partly be explained by differences in diagnoses obtained by a general practitioner compared to a specialist in dermatology. Clinical Presentation of Feline Atopic Syndrome As with canine atopic dermatitis, clinical signs of feline atopic syndrome revolve around the presence of pruritus in the cat. Comparatively, however, the distribution of pruritus and lesions is less well defined in the feline patient. With dogs, clinical signs of canine atopic dermatitis typically follow a very predictable pattern to include the face, concave pinnae, axillary and inguinal folds, ventrum, perineal skin, flexural surfaces, and paws [43, 44]. With cats, however, pruritus and lesions will generally include any one or more of the commonly recognized cutaneous reaction patterns reflecting a response to inflammation in feline skin [2]. While these patterns do not reflect a specific etiology, they often are indicative of underlying allergic skin disease. Head/Neck/Pinnal Pruritus with Excoriations Also referred to as cervicofacial pruritic dermatitis, lesions associated with this reaction pattern are restricted to the front part of the cat. From the neck directed caudally, the cat will generally appear normal. The face, ears, and neck, however, may be marked with excoriation, crusts, alopecia, and erythema (Fig. 1). In some cases, pruritus can be so severe that obvious self-trauma is apparent. VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation 457 Fig. 1 Cat with cervicofacial pruritus secondary to feline atopic syndrome Fig. 2 Cat with selfinduced alopecia secondary to feline atopic syndrome. Note barbered hair over site of forelimb amputation aligning with contralateral axillary alopecia Self-Induced Alopecia Historically, cats with self-induced alopecia (often referred to as “symmetrical alopecia,” “fur mowing,” or “barbering”) have been overdiagnosed with behavioral abnormalities and psychogenic alopecia. With this reaction patterns, cats will remove hair by excessive licking, chewing, or pulling to the point of partial to near complete alopecia of the affected body region (Fig. 2). The hairs will frequently appear broken and rough where over-grooming has occurred. Concurrent erythematous skin and excoriation may or may not be present. Miliary Dermatitis Deriving its name from millet seeds (small grains), miliary dermatitis lesions in the cat will often better be palpated as opposed to visualized. Lesions most commonly present along the neck and dorsum; however, the sparsely haired region of 458 b VetBooks.ir a A. Diesel Fig. 3 (a) Miliary dermatitis lesions on dorsum of cat with flea allergy dermatitis. (b) Miliary dermatitis lesions on head of cat with feline atopic syndrome preauricular skin can be the best location to visualize miliary dermatitis in the feline patient without having to clip the hair coat (Fig. 3a, b). When present, the lesions appear as small, pinpoint erythematous crusted papules. On palpation, the lesions will feel like small grits or grains under the skin, as if petting coarse sandpaper. Eosinophilic Skin Lesions Included in this group of lesions are eosinophilic granulomas, eosinophilic plaques, and lip (“indolent,” “rodent”) ulcers. This collection of lesions used to be referred to as the feline “eosinophilic granuloma complex”; however, this terminology has fallen out of favor with many dermatologists when describing these lesions in the cat due to their distinct clinical and histopathological appearance. While they can appear on any given body surface, eosinophilic granulomas may appear most frequently on the caudal thigh (Fig. 4a) or the ventral surface of the chin (Fig. 4b). The previous may be referred to as “linear granulomas,” while the latter may be termed “fat chin” or “pouty” cat lesions. Granulomas are typically semi-firm, rather well circumscribed, and may be seen in the presence or absence of pruritus. Additionally, granulomas may occur in the oral cavity secondary to feline atopic syndrome (Fig. 4c). Cats may initially present with clinical signs of dysphagia, drooling, decreased appetite, or even dyspnea depending on the size of the lesion present. Alternatively, they may be found on oral examination in the absence of any obvious clinical abnormalities. Lip (indolent) ulcers may also present in the absence of clinical signs. These craterous, ulcerative lesions may be unilaterally or bilaterally present on the upper lips of affected cats (Fig. 5). Extension along the philtrum to the nasal planum is a fairly common finding. Of the three lesions, eosinophilic plaques tend to be associated with severe pruritus and concurrent self-induced alopecia. The lesions may again be present on any part of the body and are most commonly visualized on the ventral abdomen. Feline Atopic Syndrome: Epidemiology and Clinical Presentation b VetBooks.ir a 459 c Fig. 4 (a) Eosinophilic granuloma lesions on caudal thighs of a cat with feline atopic syndrome. (b) Eosinophilic granuloma lesion on the chin of a cat with feline atopic syndrome. (c) Eosinophilic granuloma lesion in caudal oral cavity of cat with feline atopic syndrome. This cat had moderate dysphagia and respiratory stridor due to the size of the lesion Fig. 5 Bilateral indolent ulcer on upper lip of a cat with feline atopic syndrome VetBooks.ir 460 A. Diesel Eosinophilic plaques are generally well-circumscribed, erythematous plaque-like lesions with a glistening, moist surface. Lesions are often multifocal and may coalesce into a larger, single plaque (Fig. 6). Extra-cutaneous Clinical Signs While dermatological manifestation is the hallmark of feline atopic syndrome, other extra-cutaneous clinical signs may also present in the allergic cat. This may include allergic otitis, sinusitis, and conjunctivitis as well as feline small airway disease (“feline asthma”) in certain patients. How frequently these diseases/clinical manifestations occur concurrently, however, is unknown. As part of cervicofacial pruritic dermatitis, pinnal pruritus is a fairly common clinical finding in cats with atopic syndrome. On otoscopic examination, however, the external ear canals themselves are frequently normal in appearance. This is in contrast to dogs with canine atopic dermatitis as they frequently present with erythematous otitis externa secondary to allergic disease [2]. Commonly mistaken for ear mite infestation, many cats with atopic syndrome will present with recurrent ceruminous otitis externa, often in the absence of infectious organisms such as bacteria or yeast. This can contribute to the otic pruritus observed. Commonly reported in cats with feline atopic syndrome, sneezing may be indicative of sinusitis in allergic cats. Although uncertain the exact prevalence, some sources site this concurrent clinical finding of upward of 50% in cats with feline atopic syndrome [45]. While there is only a single report of feline allergic rhinitis documented in the veterinary literature [46], this may be under-reported since a Fig. 6 Large eosinophilic plaque on the abdomen of a cat with feline atopic syndrome. Close inspection of the lesion shows where multiple smaller plaques coalesced to form the larger lesion seen on the patient VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation 461 clinical suspicion may be addressed in the absence of a definitive (e.g., biopsy) diagnosis. However, the exact prevalence of these findings in cats with atopic syndrome is unknown since imaging studies have yet to investigate these concurrent disease presentations. As with other extra-cutaneous manifestations of allergies, the prevalence of concurrent feline asthma in cats with atopic syndrome is uncertain. Feline small airway disease or feline asthma is a complex syndrome; however, many cats have an allergic pathogenesis [22]. In a pilot study evaluating the prevalence of positive reactions to inhaled allergens in cats with small airway disease [23], the presence of concurrent or pre-existing dermatologic abnormalities was quite high, making recruitment of patients for the study difficult. This finding may indicate a higher percentage of cats with both allergic airway disease and feline atopic syndrome. In some cases, the severity of respiratory signs may, however, overshadow the presence of concurrent skin disease, or treatment for feline asthma (i.e., glucocorticoids) may control the signs of cutaneous allergy and thereby mask the true clinical appearance. Further study is warranted to better elucidate the relationship between the two disease conditions. Conclusions Feline atopic syndrome draws several parallels to canine atopic dermatitis mostly in the involvement of pruritus in this clinical diagnosis. Much uncertainty remains, however, in regard to the similarities which can be identified between the two allergic conditions in regard to clinical manifestations of disease and the particular nature of disease pathogenesis. There remains quite a good amount of information yet to be discovered with regard to the patient with feline atopic dermatitis. Compared to their canine counterpart, studies are lacking in the veterinary literature for allergic cats. References 1. Reedy LM. Results of allergy testing and hyposensitization in selected feline skin diseases. J Am Anim Hosp Assoc. 1982;18:618–23. 2. Hobi S, Linek M, Marignac G, Olivry T, Beco L, Nett C, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 3. Marsella R, De Benedetto A. Atopic dermatitis in animals and people: an update and comparative review. Vet Sci. 2017;4(3):37. 4. Peng W, Novak N. Pathogenesis of atopic dermatitis. Clin Exp Allergy. 2015;45(3):566–74. 5. Martel BC, Lovato P, Bäumer W, Olivry T. Translational animal models of atopic dermatitis for preclinical studies. Yale J Biol Med. 2017;90(3):389–402. 6. Elmose C, Thomsen SF. Twin studies of atopic dermatitis: interpretations and applications in the filaggrin era. J Allergy. 2015;2015:902359. 7. Amat F, Soria A, Tallon P, Bourgoin-Heck M, Lambert N, Deschildre A, Just J. New insights into the phenotypes of atopic dermatitis linked with allergies and asthma in children: an overview. Clin Exp Allergy. 2018;48(8):919–34. VetBooks.ir 462 A. Diesel 8. Wilhem S, Kovalik M, Favrot C. Breed-associated phenotypes in canine atopic dermatitis. Vet Dermatol. 2010;22:143–9. 9. Nuttal T. The genomics revolution: will canine atopic dermatitis be predictable and preventable? Vet Dermatol. 2013;24(1):10-8.e.3-4. 10. Moriello KA. Feline atopy in three littermates. Vet Dermatol. 2001;12:177–81. 11. Prost C. Les dermatoses allergiques du chat. Prat Méd Chir Anim Comp. 1993;28:151–3. 12. Roosje PJ, Thepen T, Rutten VP, et al. Immunophenotyping of the cutaneous cellular infiltrate after atopy patch testing in cats with atopic dermatitis. Vet Immunol Immunopathol. 2004;101:143–51. 13. Marsella R, Girolomoni G. Canine models of atopic dermatitis: a useful tool with untapped potential. J Invest Dermatol. 2009;129(10):2351–7. 14. Halliwell R, the International Task Force on Canine Atopic Dermatitis. Revised nomenclature for veterinary allergy. Vet Immuno Immunopathol. 2006;114:207–8. 15. Taglinger K, Helps CR, Day MJ, Foster AP. Measurement of serum immunoglobulin E (IgE) specific for house dust mite antigens in normal cats and cats with allergic skin disease. Vet Immunol Immunopathol. 2005;105:85–93. 16. Lauber B, Molitor V, Meury S, Doherr MG, Favrot C, Tengval K, et al. Total IgE and allergen- specific IgE and IgG antibody levels in sera of atopic dermatitis affected and non-affected Labrador- and Golden retrievers. Vet Immunol Immunopathol. 2012;149:112–8. 17. Gilbert S, Halliwell RE. Feline immunoglobulin E: induction of antigen-specific antibody in normal cats and levels in spontaneously allergic cats. Vet Immunol Immunopathol. 1998;63:235–52. 18. Reinero CR. Feline immunoglobulin E: historical perspective, diagnostics and clinical relevance. Vet Immunol Immunopathol. 2009;132:13–20. 19. Gilbert S, Halliwell RE. Production and characterization of polyclonal antisera against feline IgE. Vet Immunol Immunopathol. 1998;63:223–33. 20. Lee-Fowler TM, Cohn LA, DeClue AE, Spinkna CM, Ellebracht RD, Reinero CR. Comparison of intradermal skin testing (IDST) and serum allergen-specific IgE determination in an experimental model of feline asthma. Vet Immunol Immunopathol. 2009;132:46–52. 21. Seals SL, Kearney M, Del Piero F, Hammerberg B, Pucheu-Haston CM. A study for characterization of IgE-mediated cutaneous immediate and late-phase reactions in non-allergic domestic cats. Vet Immunol Immunopathol. 2014;159:41–9. 22. Norris Reinero CR, Decile KC, Berghaus RD, Williams KJ, Leutenegger CM, Walby WF, et al. An experimental model of allergic asthma in cats sensitized to house dust mite or Bermuda grass allergen. Int Arch Allergy Immunol. 2004;135:117–31. 23. Moriello KA, Stepien RL, Henik RA, Wenholz LJ. Pilot study: prevalence of positive aeroallergen reactions in 10 cats with small airway disease without concurrent skin disease. Vet Dermatol. 2007;18:94–100. 24. Taglinger K, Day MJ, Foster AP. Characterization of inflammatory cell infiltration in feline allergic skin disease. J Comp Pathol. 2007;137:211–23. 25. Roosje PJ, Whitaker-Menezes D, Goldschmidt MH, et al. Feline atopic dermatitis. A model for Langerhans cell participation in disease pathogenesis. Am J Pathol. 1997;151:927–32. 26. Novak N. An update on the role of human dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2012;129:879–86. 27. Roosje PJ, Koeman JP, Thepen T, et al. Mast cells and eosinophils in feline allergic dermatitis: a qualitative and quantitative analysis. J Comp Pathol. 2004;131:61–9. 28. Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol. 2011;41:298–310. 29. Jarvikallio A, Naukkarinen A, Harvima IT, et al. Quantitative analysis of tryptase- and chymase-containing mast cells in atopic dermatitis and nummular eczema. Br J Dermatol. 1997;136:871–7. 30. Beadleston DL, Roosje PJ, Goldschmidt MH. Chymase and tryptase staining of normal feline skin and of feline cutaneous mast cell tumors. Vet Allergy Clin Immunol. 1997;5:54–8. VetBooks.ir Feline Atopic Syndrome: Epidemiology and Clinical Presentation 463 31. Roosje PJ, van Kooten PJ, Thepen T, Bihari IC, Rutten VP, Koeman JP, et al. Increased numbers of CD4+ and CD8+ T cells in lesional skin of cats with allergic dermatitis. Vet Pathol. 1998;35:268–73. 32. Roosje PJ, Dean GA, Willemse T, et al. Interleukin 4-producing CD4+ T cells in the skin of cats with allergic dermatitis. Vet Pathol. 2002;39:228–33. 33. Taglinger K, Van Nguyen N, Helps CR, et al. Quantitative real-time RT-PCR measurement of cytokine mRNA expression in the skin of normal cats and cats with allergic skin disease. Vet Immunol Immunopathol. 2008;122:216–30. 34. Dunham S, Messamore J, Bessey L, Mahabir S, Gonzales AJ. Evaluation of circulating interleukin-31 levels in cats with a presumptive diagnosis of allergic dermatitis. Vet Dermatol. 2018;29:284. [abstract] 35. Szczepanik MP, Wilkołek PM, Adamek ŁR, et al. The examination of biophysical parameters of skin (transepidermal water loss, skin hydration and pH value) in different body regions of normal cats of both sexes. J Feline Med Surg. 2011;13:224–30. 36. Szczepanik MP, Wilkołek PM, Adamek ŁR, et al. Correlation between transepidermal water loss (TEWL) and severity of clinical symptoms in cats with atopic dermatitis. Can J Vet Res. 2018;82(4):306–11. 37. Sanford JA, Gallo RL. Functions of the skin microbiota in health and disease. Semin Immunol. 2013;25(5):370–7. 38. Rodrigues Hoffmann A, Patterson AP, Diesel A, Lawhon SD, Ly HJ, Elkins Stephenson C, et al. The skin microbiome in healthy and allergic dogs. PLoS One. 2014;9(1):e83197. 39. Older CE, Diesel A, Patterson AP, Meason-Smith C, Johnson TJ, Mansell J, et al. The feline skin microbiota: the bacteria inhabiting the skin of healthy and allergic cats. PLoS One. 2017;12(6):e0178555. 40. Scott DW, Miller WH, Erb HN. Feline dermatology at Cornell University: 1407 cases (1988– 2003). J Fel Med Surg. 2013;15(4):307–16. 41. Scott DW, Paradis M. A survey of canine and feline skin disorders seen in a university practice: small animal clinic, University of Montréal, Saint-Hyacinthe, Québec (1987–1988). Can Vet J. 1990;31:830–5. 42. Hill PB, Lo A, Eden CAN, Huntley S, Morey V, Ramsey S, et al. Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animal general practice. Vet Rec. 2006;158:533–9. 43. Griffin CE, DeBoer DJ. The ACVD task force on canine atopic dermatitis (XIV): clinical manifestations of canine atopic dermatitis. Vet Immunol Immunopathol. 2001;81(3–4):255–69. 44. Hensel P, Santoro D, Favrot C, Hill P, Griffin C. Canine atopic dermatitis: detailed guidelines for diagnosis and allergen identification. BMC Vet Res. 2015;11:196. 45. Foster AP, Roosje PJ. Update on feline immunoglobulin E (IgE) and diagnostic recommendations for atopy. In: August JR, editor. Consultations in feline internal medicine. 5th ed. St. Louis: Elsevier; 2006. p. 229–38. 46. Masuda K, Kurata K, Sakaguchi M, Yamashita K, Hasegawa A, Ohno K, Tsujimoto H. Seasonal rhinitis in a cat sensitized to Japanese cedar (Cryptomeria japonica) pollen. J Vet Med Sci. 2001;63:79–81. VetBooks.ir Feline Atopic Syndrome: Diagnosis Ralf S. Mueller Abstract Feline atopic syndrome is an aetiological diagnosis of a disease caused by environmental or dietary allergens. As such there is currently no single test reliably differentiating feline atopic syndrome from its differential diagnoses. This syndrome is associated with a number of clinical reaction patterns such as miliary dermatitis, eosinophilic granuloma, pruritus leading to non-inflammatory alopecia or ulcerative and crusty dermatitis. The diagnosis is confirmed by ruling out all differential diagnoses based on history and clinical examination. Hence, the diagnostic approach is different with the various reaction patterns. As adverse food reaction and flea bite hypersensitivity are differential diagnoses for all these reaction patterns, excellent ectoparasite control and an elimination diet are part of the recommended diagnostic work-up for all cats with suspected feline atopic syndrome. Depending on the clinical findings, other diagnostic tests such as cytology, Wood’s lamp, trichogram, fungal culture or biopsy may be indicated. Introduction In contrast to canine atopic dermatitis, which has distinct clinical features, feline atopic syndrome is characterized by a number of cutaneous reaction patterns that look distinctively different [1, 2]. Miliary dermatitis, eosinophilic granuloma complex or pruritus without lesions, either leading to non-inflammatory alopecia or secondary excoriations with ulceration and crusting, can all be due to feline atopic syndrome. Similar to canine atopic dermatitis, feline atopic syndrome is a diagnosis R. S. Mueller (*) Centre for Clinical Veterinary Medicine, München, Germany e-mail: dermatologie@medizinische-kleintierklinik.de © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_22 465 VetBooks.ir 466 R. S. Mueller based on history, clinical signs and exclusion of differential diagnoses [3]. However, each of the above-mentioned reaction patterns has a different list of differential diagnoses and consequently needs a slightly different approach. This chapter will discuss the differential diagnoses of the various cutaneous reaction patterns frequently associated with feline atopic syndrome as well as the diagnostic approach for each of those. General Principles of Diagnosis A thorough history and clinical examination are essential for the formulation of a list of differential diagnoses for each of the cutaneous reaction patterns seen regularly with feline atopic syndrome. Important questions to be asked depend on the individual reaction pattern and the differential diagnoses possibly responsible for it. Fleas, food or environmental allergens can cause all of the stated clinical signs and thus questions about current ectoparasite control, feeding habits, faecal consistency (when owners have access to the faeces) and attempted elimination diets are relevant for all those reaction patterns [1]. Other diagnoses are only associated with selected patterns. For example, an infestation with Otodectes cynotis has been reported as a cause of miliary dermatitis [4], but not with eosinophilic granuloma, and questions about previous ear disease and other affected animals in the household are important. Non-inflammatory alopecia may be caused by demodicosis [4] or rarely endocrine disease or alopecia areata, diseases not considered in a cat with miliary dermatitis. The age of the patient and careful questioning with regard to systemic signs may provide clinical clues for endocrine disease. Once the list of differential diagnoses and their order of priority based on history and clinical findings have been established, diagnostic tests to rule out or confirm those diagnoses are undertaken. The efforts spent to achieve a confirmed diagnosis as quickly as possible will of course also be determined by the owner and his or her willingness to invest time and money. In some patients, tests will be performed subsequently in the order of disease likelihood or necessity to rule out (e.g. a dermatophyte culture in a Persian cat), and other cat owners will choose to perform an array of tests at the same time to rule out a number of differential diagnoses fairly quickly. Once every other differential diagnosis has been ruled out, the diagnosis of feline atopic syndrome is confirmed. Approach to the Cat with Miliary Dermatitis Although miliary dermatitis (Fig. 1) is often assumed to be caused by allergic reactions against fleas and environmental or food allergens (and indeed those are the cause in the majority of cats), other causes are possible and may need to be considered in individual patients. Ectoparasites other than fleas, notably mites such VetBooks.ir Feline Atopic Syndrome: Diagnosis 467 Fig. 1 Miliary dermatitis with small crusts in a domestic shorthaired cat Table 1 Diseases causing or contributing to miliary dermatitis Allergies Infectious diseases Immune-mediated diseases Neoplastic diseases Nutritional deficiencies Flea bite hypersensitivity Environmental atopic syndrome Food-induced atopic syndrome Dermatophytosis Bacterial infection Notoedres cati Otodectes cynotis Demodex cati Pemphigus foliaceus Mast cell tumour Fatty acid deficiency as Cheyletiella blakei or Otodectes cynotis, may also lead to miliary dermatitis (Table 1). Infections with dermatophytes or bacteria may cause or contribute to clinical signs of miliary dermatitis. On rare occasions, pemphigus foliaceus and mast cell tumours can present with similar small crusted papules. Finally, some nutritional deficiencies such as a lack of essential fatty acids in the diet may cause miliary dermatitis. In most circumstances, this is unlikely with current feeding practices. Depending on the clinical history and physical examination, skin scrapings, ectoparasite control, skin cytology or biopsy and elimination diets may be indicated to work up individual cats with miliary dermatitis. Skin biopsy is the diagnostic test of choice to differentiate allergic from immune-mediated or neoplastic skin disease. However, it is less likely to be able to differentiate between ectoparasitic and allergic causes and cannot reliably differentiate causes of allergy. 468 R. S. Mueller VetBooks.ir Approach to the Cat with Pruritus Initial pruritus without lesions may lead either to non-inflammatory alopecia or to ulcerations and crusting due to self-trauma, usually in the area of the head and neck. Those reaction patterns have different possible aetiologies. Non-inflammatory alopecia (Fig. 2) is most frequently caused by flea, food or environmental allergens or any combination thereof [1, 2]. A major differential diagnosis for a pruritic cat with non-inflammatory alopecia is psychogenic alopecia [5]. Major changes in the environment, such as a physical move from countryside to a town or city, a new cat moving into the neighbourhood, a new baby or animal in the household or changes in the work hours of the family, may cause excessive licking in some cats. Consulting a veterinary behaviourist may be helpful in such cases and is recommended in those cases which do not respond to an elimination diet or flea control. In early stages of dermatophytosis, associated mild scaling and a fine papular rash may not be present or may be overlooked [6], and fungal tests such as Wood’s lamp, trichograms, cultures or PCR may be useful diagnostic options. However, keep in mind the possibility of false-positive PCR reactions due to transient environmental contamination. Very rarely, endocrine diseases such as hyperadrenocorticism may cause non-pruritic non-inflammatory alopecia in the cat, typically associated with other systemic signs [7–9]. Hormonal testing is needed in such cats. Unusual alopecias such as telogen effluvium (where a stressful event sends all hair follicles of a certain area into a synchronized telogen (the resting phase) and alopecia occurs 6–12 weeks later when the new hair is regrowing in the deep dermis) or anagen defluxion (where a severe metabolic disease or chemotherapy leads to the production of damaged hair shafts that break off within the follicular lumen leading to alopecia) can be ruled out or suspected by a thorough history. Ventral abdominal alopecia associated with demodicosis has been diagnosed in restricted geographical areas worldwide and associated with pruritic non-inflammatory alopecia (Table 2). Head and neck pruritus leading sometimes to widespread crusting and ulceration (Fig. 3) may be due to environmental allergens, but food allergens, flea bite hypersensitivity and other ectoparasite infestations such as Notoedres cati or Otodectes cynotis may also be considered [1, 2]. Secondary infections with bacteria or yeast occur frequently. Infections with dermatophytosis may be associated with pruritus if the skin is inflamed. If there is a previous clinical history of an Fig. 2 Non-inflammatory hypotrichosis and alopecia on the ventrum of a 7-year-old, male castrated domestic shorthaired cat Feline Atopic Syndrome: Diagnosis VetBooks.ir Table 2 Diseases causing alopecia in the cat 469 Allergies Psychogenic diseases Infectious diseases Endocrine diseases Drug reaction Miscellaneous diseases Flea bite hypersensitivity Environmental atopic syndrome Food-induced atopic syndrome Psychogenic alopecia Dermatophytosis Demodex cati Hypothyroidism Hyperadrenocorticism Methimazole-induced alopecia Telogen effluvium Anagen defluxion Fig. 3 A large crust and excoriations in a cat with severe pruritus on the head. (Courtesy of Dr. Chiara Noli) upper respiratory tract infection and mucosal surfaces are affected as well, viral infections with feline herpes- or calicivirus should be considered. On rare occasions cowpox virus infections may also lead to variably pruritic, ulcerative and crusty skin disease with fever and anorexia [10]. Cowpox is inoculated through the bite wound of a rodent and initially a solitary lesion develops. Fever and multifocal cutaneous lesions result from a subsequent viremia. Such cats may be highly infectious and have been reported to die from viral pneumonia. PCR testing of crusts is the diagnostic tool of choice, it is fast, and the poxvirus inclusions are rich in the crust. On histopathology, cowpox virus is identified through intracytoplasmic eosinophilic inclusion bodies and herpes virus through an eosinophilic dermatitis, folliculitis and furunculosis and with careful searching for amphophilic intranuclear inclusion bodies. Pruritus may be caused by flea, food or environmental allergens, but other diseases such as medication reactions or, in older cats, paraneoplastic pruritus may also be considered. If a hyperthyroid cat develops pruritus on methimazole, discontinuation VetBooks.ir 470 R. S. Mueller of the medication typically leads to a quick resolution of the self-trauma, and an alternative treatment for hyperthyroidism should be elected. In older pruritic cats, particularly with Malassezia infections of the head or neck, paraneoplastic skin disease should be considered. Depending on history and physical examination, ultrasonography, radiography (and/or CT/MRI), lymph node aspirates, complete blood counts and serum biochemistry may all be indicated when paraneoplastic pruritus is considered. pproach to the Cat with Lesions of the Eosinophilic A Granuloma Complex Lesions of the eosinophilic granuloma complex may be observed with feline atopic syndrome [1, 2]. Indolent lip ulcers (Fig. 4) (often asymmetrical ulcers frequently on the mucosal margin of the upper lip and often covered with a thick yellowish adherent exudate), eosinophilic granulomas (Fig. 5) (papular to linear lesions, often eroded or ulcerated, frequently found on the caudal thighs) and (typically highly pruritic) eosinophilic plaques (Fig. 6) found on the ventral abdomen and inner thighs can all be caused by flea, food or environmental allergens, and thus Fig. 4 Indolent ulcer on the upper lip of a 6-year-old female domestic shorthaired cat. (Courtesy of Dr. Chiara Noli) Fig. 5 A linear lesion of eosinophilic granuloma on the thigh. (Courtesy of Dr. Chiara Noli) VetBooks.ir Feline Atopic Syndrome: Diagnosis 471 Fig. 6 Same cat as in Fig. 4: a large eosinophilic plaque on the abdomen. (Courtesy of Dr. Chiara Noli) Fig. 7 Impression smear from a plaque: neutrophils with intra- and extracytoplasmatic cocci and rod-shaped bacteria. The latter probably origin from the oral flora (Diff Quick, 1000×). (Courtesy of Dr. Chiara Noli) ectoparasite control and an elimination diet are part of the thorough diagnostic work-up of any cat with lesions belonging to the eosinophilic granuloma complex. On occasion, squamous cell carcinoma may be a differential diagnosis, particularly in older cats with lesions in non-pigmented or sparsely haired areas of the head. In those cats, a biopsy is also indicated. Ruling Out Skin Infections Although skin infections are rarer in cats than in dogs, they do occur in the feline species and may contribute significantly to both pruritus and clinical signs. They need to be recognized and treated to achieve optimal therapeutic outcome. A cytologic evaluation of an impression smear is the test of choice to identify bacterial or yeast infections [11]. If the skin and crusts are very dry, a better yield is often achieved by removing a few crusts and obtaining cytology from the underlying surface of the crusts. Neutrophils with intracellular bacteria (Fig. 7) confirm a bacterial skin infection without a doubt. The presence of bacteria or yeast has to be VetBooks.ir 472 R. S. Mueller Fig. 8 Numerous Malassezia yeasts from the skin of an allergic cat (Diff Quick 400×). (Courtesy of Dr. Chiara Noli) interpreted in light of the numbers of organisms, clinical signs and the sampling site. Large numbers of Malassezia spp. yeasts (Fig. 8) have been reported to be a possible clinical clue for internal malignancies in the cat; however, they can also be found with allergic skin disease. Examination of the skin with a Wood’s lamp, trichograms, fungal cultures or PCR for fungal antigens may be useful in patients with possible dermatophytosis. Ruling Out Ectoparasites It is important to identify the type of ectoparasite control the owner conducts, which exact product is administered, how often and to which of the animals in the household. Some of the products on the market have a high efficacy for fleas and ticks; others can also be used to treat mite infestations. An effective and complete ectoparasite control should address not just fleas but also mites. Macrocyclic lactones or isoxazolines are examples of such ectoparasiticides. Whether additional environmental control is needed in addition to regular adulticides will depend on the individual patient, environment and climate. Flea proliferation is facilitated by warm and humid climates. With large numbers of immature stages in a conducive environment, spraying the house or apartment with an insect growth regulator such as methoprene or pyriproxyfen will hasten clinical improvement in affected cats. Similarly, such environmental control may be needed in households with multiple animals and consequently a large environmental load of immature flea stages such as eggs, larvae and pupae. Performing an Elimination Diet At this point, an elimination diet is the only reliable test to identify feline atopic syndrome caused by food antigens [12]. This involves – theoretically – the feeding of a protein source the animal has never received before. In cats, however, VetBooks.ir Feline Atopic Syndrome: Diagnosis 473 that seemingly simple condition is frequently difficult to achieve. First, many cats receive a far more varied diet than their canine counterparts, and it is not unusual that feline patients get a different protein source every day of the week. Second, cats are creatures of habit and more easily refuse to eat a new diet than dogs. In addition, refusal to eat for a few days increases the risk of development of hepatic lipidosis in the cat, and starvation until compliance is achieved is absolutely not recommended. Consequently, several different food sources may have to be trialled before a successful elimination diet can be conducted, and the author advises owners to have the choice of two protein sources available should the cat suddenly decide not to eat. Owners can choose between a home-cooked elimination diet, commercial selected protein diets and hydrolysed diets. Many commercial selected protein diets have been shown to be contaminated with other, off-label protein sources, although the clinical relevance of those contaminations has not been evaluated. Consequently, the author prefers home-cooked or extensively hydrolysed diets for the diagnosis of food-induced feline atopic syndrome. Cats are obligate carnivores, so that when choosing a home-cooked diet, they can be fed pure protein. A carbohydrate source is not essential and may decrease palatability and compliance in cats. Ideally, the protein source is phylogenetically distant from the originally fed protein. If the cat received a predominantly chicken- and turkey-based cat food, then switching, for example, to duck may not be as suitable as rabbit or horse. Similarly, if the cat received a beef- or lamb-based diet, then deer or goat may not be the ideal alternative, as the chance of cross-reactivity between those allergens is probably much higher than if ostrich or crocodile is chosen for that particular cat. However, clinical cross-reactivities have not been established in cats with food allergies at this point in time. The diet should be fed exclusively for approximately 8 weeks, during which time more than 90% of the cats with adverse food reactions will improve [13]. In those 8 weeks, no other protein sources should be permitted. A cat with access to outdoors technically needs to be confined indoors during the entire diet. If that is not possible and the cat does not respond, then an adverse food reaction cannot reliably be ruled out. However, this may indeed be too stressful for the cat. In the author’s opinion, it may be still worthwhile conducting an elimination diet in some indoor-outdoor cats, because of the possibility that just a reduction of the amount of allergy-inducing protein may lower the pruritic threshold. In a multi-cat household, all cats should receive the elimination diet or the patient should be fed completely separately to avoid unintended intake of a different protein source. If there is no clinical improvement after 8 weeks of an appropriate elimination diet, then an adverse food reaction is very unlikely. If however there was clinical improvement, then a re-challenge with the previous diet is essential as this improvement may be due to the diet, but may also be due to seasonal changes, different or more reliably administered concurrent treatments and other reasons not related to the diet. If the re-challenge with the previous diet leads to recurrence of clinical signs, which resolve again when the elimination diet is fed, the diagnosis of adverse food reaction is confirmed. Long-term, the offending allergen(s) can be identified by sequential re-challenges with individual proteins, the cat may be fed a commercial VetBooks.ir 474 R. S. Mueller hydrolysed or selected protein diet, or the elimination diet may be continued. If the owner opts for the latter, it is recommended to consult a veterinary nutritionist in order to balance the home-prepared diet and avoid nutritional deficiencies. Conclusion Feline atopic syndrome is an aetiological diagnosis associated with a number of clinical reaction patterns such as miliary dermatitis, eosinophilic granuloma, pruritus leading to non-inflammatory alopecia or ulcerative and crusty dermatitis. The diagnosis is confirmed by ruling out all differential diagnoses based on history and clinical examination. As adverse food reaction and flea bite hypersensitivity are differential diagnoses for all these reaction patterns, excellent ectoparasite control and an elimination diet are part of the recommended diagnostic work-up for all cats with suspected feline atopic syndrome. Depending on the clinical findings, other diagnostic tests such as cytology, Wood’s lamp, trichogram, fungal culture or biopsy may be indicated. References 1. Hobi S, Linek M, Marignac G, Olivry T, Beco L, Nett C, et al. Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses. Vet Dermatol. 2011;22:406–13. 2. Ravens PA, Xu BJ, Vogelnest LJ. Feline atopic dermatitis: a retrospective study of 45 cases (2001–2012). Vet Dermatol. 2014;25:95–102, e27-8 3. DeBoer DJ, Hillier A. The ACVD task force on canine atopic dermatitis (XV): fundamental concepts in clinical diagnosis. Vet Immunol Immunopathol. 2001;81:271–6. 4. Scheidt VJ. Common feline ectoparasites part 2: Notoedres cati, Demodex cati, Cheyletiella spp. and Otodectes cynotis. Feline Pract. 1987;17:13–23. 5. Waisglass SE, Landsberg GM, Yager JA, Hall JA. Underlying medical conditions in cats with presumptive psychogenic alopecia. J Am Vet Med Assoc. 2006;228:1705–9. 6. Scarampella F, Zanna G, Peano A, Fabbri E, Tosti A. Dermoscopic features in 12 cats with dermatophytosis and in 12 cats with self-induced alopecia due to other causes: an observational descriptive study. Vet Dermatol. 2015;26:282–e63. 7. Boord M, Griffin C. Progesterone secreting adrenal mass in a cat with clinical signs of hyperadrenocorticism. J Am Vet Med Assoc. 1999;214:666–9. 8. Rand JS, Levine J, Best SJ, Parker W. Spontaneous adult-onset hypothyroidism in a cat. J Vet Intern Med. 1993;7:272–6. 9. Zerbe CA, Nachreiner RF, Dunstan RW, Dalley JB. Hyperadrenocorticism in a cat. J Am Vet Med Assoc. 1987;190:559–63. 10. Appl C, von Bomhard W, Hanczaruk M, Meyer H, Bettenay S, Mueller R. Feline cowpoxvirus infections in Germany: clinical and epidemiological aspects. Berliner und Münchner Tierärztliche Wochenschrift. 2013;126:55–61. 11. Mueller RS, Bettenay SV. Skin scrapings and skin biopsies. In: Ettinger SJ, Feldman EC, Cote E, editors. Textbook of veterinary internal medicine. Philadelphia: W.B. Saunders; 2017. p. 342–5. 12. Mueller RS, Unterer S. Adverse food reactions: pathogenesis, clinical signs, diagnosis and alternatives to elimination diets. Vet J. 2018;236:89–95. 13. Olivry T, Mueller RS, Prelaud P. Critically appraised topic on adverse food reactions of companion animals (1): duration of elimination diets. BMC Vet Res. 2015;11:225. VetBooks.ir Feline Atopic Syndrome: Therapy Chiara Noli Abstract Feline allergic dermatitis is a chronic disease and allergen avoidance, when possible, is the best management option. If this is not possible, then a combination of aetiologic, symptomatic, topical, antimicrobial and nutritional therapy is implemented, depending on the individual case. Aetiologic therapy is based on allergy test and hyposensitization, which will be curative only in a minority of cases. All other cases will need some sort of symptomatic therapy, possibly avoiding long-term administration of glucocorticoids. Alternative systemic treatments include ciclosporin, antihistamines, oclacitinib, palmitoylethanolamide, maropitant and PUFAs: not all of these are effective in every case and some are not registered for the cat. Topical treatments are not easy to apply in cats and only a few studies confirm their efficacy. The pros and cons of allergy testing and hyposensitization, and of topical and/or systemic symptomatic treatment will be discussed in this chapter. Introduction Feline allergic dermatitis is a chronic disease. The clinician must make the client understand that unless the offending allergen(s) are identified and removed, a cure is rarely possible. The keys to a successful management of allergic dermatitis are client education, long-term commitment to the treatment protocol and a combination of aetiologic, symptomatic, topical, antimicrobial and nutritional therapy. The choice of the therapeutical plan will depend on the individual case, that is, on both cat (severity of the lesions and temper of the patient) and owner (economical possibilities, patience, time to devote to the cat, personal preferences). The pros and cons C. Noli (*) Servizi Dermatologici Veterinari, Peveragno, Italy © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_23 475 VetBooks.ir 476 C. Noli of allergy testing and hyposensitization, and of topical and/or systemic symptomatic treatment should be clearly explained, including possible combinations – and costs – to help the owner make an informed choice. A practical guidance on how to therapeutically approach allergic cats is offered in Box 1. Box 1: Practical Therapeutical Approach to the Pruritic Cat 1. Diagnostic period (from first presentation to end of elimination diet): –– Oral/topical flea control is advised in every case. –– For non-seasonal pruritus, the cat should undergo a 2-month-long elimination diet, better if with hydrolysed food. –– If pruritus is important and needs to be decreased, in the meanwhile the cat can be administered short-acting oral corticosteroids at tapering doses possibly every other day for the first 6 weeks. As an alternative oclacitinib or maropitant can be considered. At this stage ciclosporin should be avoided, as the lag time is very long and it takes also a long time for pruritus to come back after withdrawal. This makes it difficult to evaluate the diet. 2. First months of allergen specific immunotherapy (ASIT): –– Oral/topical flea control is advised in every case during the whole ASIT period. –– If pruritus is mild to moderate, consider antihistamines and/or ultramicronized PEA, EFAs, dermatological food, and topical hydrocortisone aceponate. –– If these do not work or if pruritus is moderate to severe, then consider ciclosporin or oclacitinib or maropitant during the first few months of ASIT (induction phase). While systemic corticosteroids can be administered for a few days at the beginning of the ASIT phase (particularly if ciclosporin is chosen as maintenance therapy), their long-term use should be avoided, as they could possibly interfere with the desensitization mechanism of ASIT. Every 2–3 months, antipruritic therapies could be withdrawn to better evaluate ASIT efficacy. 3. Long-term symptomatic management: –– Oral/topical flea control is advised in every case. –– If pruritus is mild to moderate, consider antihistamines and/or ultramicronized PEA, EFAs, dermatological food, and topical hydrocortisone aceponate, together or in combination. VetBooks.ir Feline Atopic Syndrome: Therapy 477 –– If these do not work or if pruritus is moderate to severe, then consider long- term ciclosporin administration. Corticosteroids can be associated in the first 2 weeks. –– If ciclosporin is not an option (e.g. for g.e. upset), then alternatives are low- dose corticosteroids given every other day (better if associated with steroid-sparing products, such as antihistamines, EFA or ultramicronized PEA) or oclacitinib or maropitant. 4. Management of the flare: –– Flares are best managed with short courses (5–15 days) of high-dose corticosteroids. Long-term managements (item no. 3) should then be instituted afterwards, if possible. Therapy of Allergic Dermatitis and Quality of Life Pruritus and self-induced skin lesions due to licking and scratching have a significant negative impact on the cat’s and the owner’s quality of life (QoL) [1], and therapy aiming at decreasing discomfort should be considered from the very first consultation. However, in two studies on the treatment of feline allergy, decrease of pruritus and lesions was always greater than improvement of QoL [2, 3]. This is due to the fact that administration of therapies and repeated visits to the veterinarian have a negative impact on the QoL of both cats and owners, as treating cats is certainly more difficult and a bigger source of psychological stress than treating dogs. This fact should be considered when designing a therapeutic plan for the allergic feline patient, and the plan should be sustainable by the cat and owner over a long period of time. Way of administration (oral, topical, injectable), formulation (tablets, oral liquid, lotion, spray) and frequency should be tailored to the individual patient and owner. Feeding a “dermatological” diet and/or essential fatty acids and/or palmitoylethanolamide (PEA) supplements mixed with food may be a non-traumatic way of decreasing inflammation and pruritus and the need (dose and frequency) of other antipruritic drugs. Aetiologic Therapy Identification of Allergens: Allergy Testing in Cats Allergy testing is necessary for the identification of the allergens putatively responsible for pruritus and skin lesions observed in hypersensitive cats, but it cannot be used to diagnose allergy per se, as several healthy cats show positive results and VetBooks.ir 478 C. Noli some allergic ones have negative tests [4–7]. Intradermal testing as used in dogs is of limited value in the feline species, because wheals are small, soft and transient and tests are difficult to interpret. The use of fluorescein may improve readability and reliability of intradermal tests [8, 9]. One problem with feline allergy skin testing is that, until now, allergen solutions standardized for the dog’s skin were used in cats, with limited knowledge regarding their suitability. Initial investigations have been published on allergen threshold concentrations in cats, albeit only for pollens and in healthy animals [10]. A further problem is that all cats need to be anaesthetized, as stress-related cortisol release interferes with wheal formation [11]. In order to overcome these problems, percutaneous (prick) testing is currently object of investigation in cats and is perceived to be a good alternative to intradermal testing [12, 13], but no kit is yet commercially available specific to the feline species. As in dogs, intradermal allergy tests should not be performed in cats being treated with corticosteroids. Serum testing is easier to perform and is offered by several laboratories over the world. It has the advantage of being easy to carry out (just one blood sample), does not need anaesthesia and can be performed in cats treated with corticosteroids. While in vitro allergy tests are not able to differentiate allergic from normal cats [4–7], they can be useful for the choice of the allergens to be included in the ASIT solution. There are no studies determining that one methodology is preferable over another one. The frequently used and well-studied method based on the cloned alpha chain of the human high-affinity IgE receptor (FcE-RI) (Allercept®; Heska AG, Fribourg, Switzerland) can also be used in cats. A recent study found a strong agreement between results of a rapid screening immunoassay (Allercept® E-Screen 2nd Generation; Heska AG, Fribourg, Switzerland) and the complete Allercept panel; the screening assay may thus be beneficial for predicting the results of the complete-panel serum allergen-specific IgE assay [4]. Allergen Avoidance Allergen avoidance is useful if the offending allergens have been correctly identified. Cats with indoor allergies (e.g. against house dust mites such as Dermatophagoides spp. and storage mites such as Tyrophagus, Acarus and Lepidoglyphus spp.) or danders can be allowed to spend more time outdoors. As house dust mite levels are much higher in bedrooms than in the rest of the house, limiting the cat’s access to these rooms may be of help. In the case of indoor allergens, frequent vacuuming with a “high-efficiency particle air filter” (HEPA) vacuum cleaner may reduce the allergen load, or protective furniture covers designed for human asthmatics may be of value. Sprays or foggers (devices that produce a fine mist) containing acaricidal agents or insect growth regulators may be helpful in cases of house dust/storage mite allergy. Using benzoyl-benzoate sprays on a regular basis on beddings, carpets, rugs, furniture, etc. not only kills the mites but also degrades their metabolites (allergens). One study on house dust-/storage mite-sensitive dogs showed that the use of benzyl benzoate spray at home induces 48% resolution and 36% improvement of pruritus [14]. Unfortunately there are no studies yet on allergen avoidance in cats. Feline Atopic Syndrome: Therapy 479 VetBooks.ir Immunotherapy Allergen-specific immunotherapy (ASIT) is the aetiological treatment of choice in cases where the duration of pruritus is longer than 4 months a year. Allergens are administered at increasing concentration and dose and at decreasing frequency, generally by subcutaneous injection. The mechanism of action of immunotherapy has not been investigated in cats. In dogs and humans, it seems that a shift from a Th2- to a Th1-biased immune response and increase in T-regulatory lymphocytes is responsible for the development of tolerance [15]. Protocols vary depending on the producer and adjuvant. ASIT is considered safe and effective in cats, with good to very good responses (improvement by at least 50%) achieved in 50–80% of treated patients [16–20]. Adverse events such as increased pruritus or anaphylaxis are considered less common than in dogs [17]. As in dogs, clinical results measured by a decrease in pruritus and skin lesions are seen anywhere from 3 to 18 months after starting treatment. Thus, during the initial phase of immunotherapy, symptomatic treatment may be needed. If the treatment is effective, ASIT maintenance therapy is given for the rest of the patient’s life. Only a proportion of the cases will be controlled by immunotherapy alone, while others will require adjunctive symptomatic therapy for at least part of the year. In a yet unpublished retrospective study conducted by the author, about 10% of the cats could achieve remission of the allergy after 4–5 years and could withdraw ASIT without relapses. A similar observation was also reported by Vidémont and Pin [21]. An alternative sublingual administration option is currently available, with anecdotal efficacy similar to the subcutaneous way; however there are no published reports yet in cats. Rush immunotherapy (administering the whole induction phase in a few hours, under medical control) was investigated in a small number of cats and was considered safe and effective [22]. Symptomatic Therapy Doses, administration and adverse effects of the drugs mentioned hereunder are summarized in Table 1. Glucocorticoids Glucocorticoids are very effective in suppressing the signs of allergic dermatitis. Pharmacological data on glucocorticoids in felines are scarce: cats seem to need higher doses than dogs, as they have half the density of glucocorticoid receptors in the skin and liver [23] and metabolize the active prednisolone better than the prodrug prednisone [24]. Usual protocols suggest to administer oral prednisolone at 1–2 mg/kg or oral methylprednisolone 0.8–1.6 mg/kg daily until remission of pruritus (usually Dose Induction phase q24h: 1–2 mg/kg 0.8–1.6 mg/kg 0.1–0.2 mg/kg 0.1–0.2 mg/kg Maintenance phase: 1/2 to 1/4 of the induction dose q48-72 h 7 mg/kg q24h the first month, then q48h the second month, then twice weekly as maintenance dose, if signs are under control 1 mg/kg q12h Palmitoylethanolamide 10–15 mg/kg q24h Also in association with glucocorticoids as sparing agent Maropitant 2 mg/kg q24h Oclacitinib (off-label use) Ciclosporin Oral antipruritic drug Glucocorticoids: Prednisolone Methylprednisolone Triamcinolone Dexamethasone None No information available for long-term use. Liver and heart disease Mild pruritus and eosinophilic granuloma complex Pruritus No information available for use longer than 2–4 weeks Limited information available. Increase kidney values in some cats in one study, not observed in another. Close monitoring is necessary. None Transitory vomit and/or diarrhoea (24%), weight loss, gingival hyperplasia (2%), hepatic lipidosis (2%), systemic toxoplasmosis Kidney disease, liver disease, positive FIV and/or FeLV status, malignancies, eating raw meat, hunting and eating the preys No information available. As a matter of caution the same as ciclosporin, suspect kidney disease Long-term use to keep pruritus and lesions in remission Quick decrease of pruritus without the use of glucocorticoids Side effects Skin fragility syndrome, diabetes mellitus, congestive heart failure, polyuria and polydipsia, increased susceptibility to bladder and skin infections, demodicosis and dermatophytosis Contraindications Diabetes, kidney disease, liver disease, positive FIV and/or FeLV status Indication Quick decrease of pruritus and inflammation, resolution of lesions of the eosinophilic granuloma complex Table 1 Main antipruritic and anti-inflammatory drugs used for feline allergic dermatitis. Antihistamines are reported in Table 2 VetBooks.ir 480 C. Noli VetBooks.ir Feline Atopic Syndrome: Therapy 481 3–15 days), and then the dose is reduced to every other day and then further reduced every week to the lowest dose that will control the clinical signs (generally 0.5– 0.1 mg/kg every other day). If prednisolone or methylprednisolone do not seem to be effective, a good alternative in cats is oral dexamethasone or triamcinolone (both at 0.1–0.2 mg/kg), which should then be tapered to 0.02–0.05 mg/kg every second to third day for maintenance therapy. The use of methylprednisolone and triamcinolone at the doses mentioned above did not cause an increase of fructosamine above the reference range, while triamcinolone caused a higher increase of amylase compared to methylprednisolone [25]. The use of repositol methylprednisolone acetate (usually 15–20 mg/cat, SC), whose duration of action ranges from 3 to 6 weeks, should be considered only for refractory cats, when oral administration is not possible. Repeated repositol injections appear to become less and less effective with time, so that increased frequency and/or higher doses may become necessary, with increased risks of adverse effects development. In these cases, alternative therapies (such as oral or injectable ciclosporin) should be considered. Cats are usually considered to tolerate glucocorticoids well; however adverse effects can occur and can be severe [26]. Among these there are cutaneous atrophy with skin fragility (Fig. 1), congestive heart failure, increased susceptibility to diabetes mellitus (particularly in obese cats), polydipsia and polyuria and increased susceptibility to bladder and skin infections, including development of dermatophytosis and demodicosis. A recent study, however, found no evidence of bacteriuria in cats treated with long-term oral or repositol glucocorticoids [27]. Hydrocortisone aceponate topical spray is useful to treat localized pruritus and reduce the need for systemic medication. This product has been proven to cause minimal thinning of the skin and local immunosuppression and has very low systemic absorption in dogs. An open pilot trial on ten cats determined that it is able to improve pruritus and skin lesions in allergic felines and keep them under control with daily or every other day maintenance administration [28]. Fig. 1 Large ulceration due to skin fragility in a cat being treated with 20 mg/ cat injectable methylprogesterone acetate once monthly for 5 consecutive months. The cat has completely recovered after withdrawal of the drug 482 C. Noli VetBooks.ir Ciclosporin Ciclosporin is a polypeptide derived from the fungus Tolypocladium inflatum. Its mode of action is by inhibition of calcineurin. It has a variety of immunological effects on multiple components of the skin immune system and is active in the acute and chronic phase of allergic dermatitis. Ciclosporin has the same efficacy as prednisolone in the control of clinical signs of allergic dermatitis in cats [29]. Significant reduction in pruritus should be expected in 75–85% of cases within 1 month of treatment [30]. The initial oral dose in cats is 7 mg/kg/day [31]. This dose should be administered for at least 1 month before, if effective, tapering it to every other day. After another month of successful every other day administration, tapering to twice weekly can be tried. About 15% and 60% of cats with skin allergy can be kept under control, respectively, with every other day or twice weekly administration [32, 33]. A lag period of about 2–3 weeks, in which no response is seen, occurs after ciclosporin treatment is started, and owners should be warned about this. In dogs, association of 3 weeks of prednisone or oclacitinib with ciclosporin, to quickly decrease pruritus during the lag phase, has been described, [34, 35], but no such data are available for the feline species. The proprietary feline product (Atopica® for Cats, Elanco) is a microemulsified ciclosporin liquid formulation (100 mg/ml), which cannot be mixed with water. To maximize absorption, ciclosporin should be administered 2 hours before a meal; however recent data suggested that giving ciclosporin with food does not alter clinical outcomes [36]. This formulation is not always palatable when mixed with food, and when administered directly in the mouth it can cause hypersalivation in some subjects. A syringe of fresh water may be dispensed after ciclosporin administration in order to overcome this problem. The successful use of injectable ciclosporin (50 mg/ml) at the dose of 2.5–5 mg/kg every 24–72 h was recently described [37] and could be considered for the treatment of refractory cats. Ciclosporin is usually well tolerated by cats. Reported adverse effects are transitory vomiting and/or diarrhoea in up to one fourth of the cases, so that the owners should be warned about their possible occurrence [38]. The co-administration of maropitant (2 mg/kg) with ciclosporin during the first 2–3 weeks has been anecdotally suggested to decrease vomiting and provide a quick relief of pruritus (see later for anti-pruritic effects of maropitant). Other described adverse effects are weight loss (16%) and rarely gingival hyperplasia (Fig. 2), anorexia and hepatic lipidosis (each 2% of the cases) [38]. Cats should be FIVFeLV negative and should not be allowed to hunt and eat raw meat, due to the risk of developing fatal toxoplasmosis [39]. Preventive or concurrent (during therapy) measurement of IgG and/or IgM anti-Toxoplasma serum titres does not seem to be useful to predict the development of toxoplasmosis. Clinicians should be alerted by the development of any neurologic and/or respiratory sign or significant weight loss (over 20%) in cats treated with ciclosporin. VetBooks.ir Feline Atopic Syndrome: Therapy 483 Fig. 2 Gingival hyperplasia in a cat being treated with daily ciclosporin at 10 mg/kg for 3 months. The lesions greatly improved when the dose was lowered to 5 mg/ kg every other day Table 2 Oral antihistamines reported to be used in allergic cats against pruritus Antihistamine Amitriptyline Cetirizine Chlorpheniramine Clemastine Cyproheptadine Dose 5–10 mg/cat q12-24 h 1 mg/kg or 5 mg/cat q24h 2–4 mg/cat q8-24h 0.25–0.68 mg/cat q12h 2 mg/cat q12h Diphenhydramine 1–2 mg/kg or 2–4 mg/cat q8-12h Fexofenadine 2 mg/kg up to 30–60 mg/cat q24h Hydroxyzine 5–10 mg/cat q8-12h Oxatomide 15–30 mg/cat q12h Promethazine 5 mg/cat q24h Side effects Sleepiness Sleepiness, soft stools Sleepiness, vomit, behavioural disturbances Reported efficacy (% of cats controlled) Up to 41% Up to 73% Up to 50% Up to 40% Behavioural disturbances Up to 50% Antihistamines Antihistamines inhibit the action of histamine by competitively blocking H1 receptors. As in dogs, the response to antihistamine therapy is variable, and it may be necessary to try several different agents for a period of 15 days each to determine which, if any, is more effective. The efficacy in terms of percentage of animals responding to antihistamines in cats is reported (in old, uncontrolled studies, summarized by Scott 1999 [40]) to be between 20% and 73% (Table 2). VetBooks.ir 484 C. Noli In particular, cetirizine has been object of recent investigations in cats. Pharmacological studies determined that cetirizine is orally well absorbed in cats and is able to maintain high plasma concentrations for at least 24 h [41]. In an open study, 5 mg/cat q24h determined a reduction in pruritus in 41% (13/32) of allergic cats; however only a minority (1/13) of these improved more than 50%, while the majority (10/13) improved less than 25% [42]. A subsequent randomized, double- blinded, placebo-controlled, crossover trial on the use of cetirizine 1 mg/kg q24h in 21 allergic cats confirmed that only 10% of cats improved by more than 50% with cetirizine versus 20% of placebo-treated patients, with no statistical difference between groups for pruritus or lesions [43]. Oclacitinib Oclacitinib (Apoquel®, Zoetis) is a JAK1 inhibitor registered for dogs, able to block intracellular metabolic pathways leading to the allergic activation of inflammatory cells and keratinocytes and to the elicitation of pruritus in neural fibres. Recently, the offlabel use of oclacitinib in cats was investigated in a pilot [44] and in a methylprednisolone-controlled study [3]. Oclacitinib given at 1 mg/kg every 12 h has an efficacy similar to that of methylprednisolone given at the same dose, albeit with no obvious advantage. Given for 1 month, it was generally well tolerated; however mild increases in kidney values were observed in some cats [3]. In another study no clinical, hematological or biochemical alterations were observed in cats taking oclacitinib 1 or 2 mg/kg twice daily for 28 days [45]. Oclacitinib could be a useful alternative treatment when glucocorticoids are contraindicated and a rapid relief of pruritus is required. Readers should be warned that oclacitinib is not registered in cats and that its long-term safety is not known in this species. Regular haematology and biochemistry monitoring are advised for long-term maintenance therapies. Palmitoylethanolamide (PEA) Palmitoylethanolamide (PEA) is a natural-occurring bioactive lipid present in both animals and plants. PEA is produced by several different cell types in response to tissue damage and acts by controlling the functionality of mast cells (it inhibits degranulation) and other inflammatory cells such as macrophages and keratinocytes. Consequently, PEA decreases skin inflammation and nerve sensitization in animals with allergic dermatitis. An open pilot study on 17 cats with eosinophilic granuloma and eosinophilic plaque showed that PEA (10 mg/kg q24h for 30 days) improved pruritus, erythema and alopecia in 64.3% of cats and reduced the extent and severity of eosinophilic plaques and granulomas in 66.7% [46]. Recently a product containing ultramicronized PEA (PEA-um) with improved bioavailability and efficacy was released to the international veterinary market. A multicentre, placebo-controlled, randomized trial determined a glucocorticoid sparing effect of PEA-um (15 mg/kg q24h) in cats with non-seasonal allergic dermatitis [47]. In the same study, PEA-um was showed to be able to prolong the effects of a short course of oral glucocorticoids with virtually no significant adverse effects. Feline Atopic Syndrome: Therapy 485 VetBooks.ir Maropitant Maropitant is a neurokinin-1 receptor antagonist, able to block the interaction of substance P, a pruritogenic neurokinin, to its receptor. In an open pilot study at the dose of 2 mg/kg, it has been reported to be effective against pruritus and lesions in 11/12 allergic cats [48]. Maropitant was well tolerated if administered once daily for 2–4 weeks. There is no information about its safety for a long-term treatment. Omega-3 and Omega-6 Fatty Acid Supplementation There are only few old and uncontrolled studies investigating the efficacy of essential fatty acids (EFA) in miliary dermatitis and lesions of eosinophilic granuloma in cats [49–52]. These publications reported efficacy in 40–60% of treated animals. A lag period of 6–12 weeks occurs, before any benefits are seen. Probably, only a small minority of patients can be controlled with fatty acid therapy alone. EFA may have glucocorticoid- or ciclosporin-sparing effects, as determined in dogs, but no studies were conducted in cats to confirm this. Feeding a good dermatological diet may be an effective way of supplementing EFAs in allergic cats. References 1. Noli C, Borio S, Varina A, et al. Development and validation of a questionnaire to evaluate the quality of life of cats with skin disease and their owners, and its use in 185 cats with skin disease. Vet Dermatol. 2016;27:247–e58. 2. Noli C, Ortalda C, Galzerano M. L’utilizzo della ciclosporina in formulazione liquida (Atoplus gatto®) nel trattamento delle malattie allergiche feline. Veterinaria (Cremona). 2014;28:15–22. 3. Noli C, Matricoti I, Schievano C. A double-blinded, randomized, methylprednisolone controlled study on the efficacy of oclacitinib in the management of pruritus in cats with nonflea nonfood induced hypersensitivity dermatitis. Vet Dermatol. 2019;30:110–e30. 4. Diesel A, DeBoer DJ. Serum allergen-specific immunoglobulin E in atopic and healthy cats: comparison of a rapid screening immunoassay and complete-panel analysis. Vet Dermatol. 2011;22:39–45. 5. Bexley J, Hogg JE, Hammerberg B, et al. 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J Feline Med Surg. 2016;18:889–97. 32. Steffan J, Roberts E, Cannon A, et al. Dose tapering for ciclosporin in cats with nonflea- induced hypersensitivity dermatitis. Vet Dermatol. 2013;24:315–22. 33. Roberts ES, Tapp T, Trimmer A, et al. Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis. J Feline Med Surg. 2016;18:898–905. 34. Panteri A, Strehlau G, Helbig R, et al. Repeated oral dose tolerance in dogs treated concomitantly with ciclosporin and oclacitinib for three weeks. Vet Dermatol. 2016;27:22–e7. VetBooks.ir Feline Atopic Syndrome: Therapy 487 35. Dip R, Carmichael J, Letellier I, et al. Concurrent short-term use of prednisolone with cyclosporine A accelerates pruritus reduction and improvement in clinical scoring in dogs with atopic dermatitis. BMC Vet Res. 2013;3(9):173. 36. Steffan J, King S, Seewald W. Ciclosporin efficacy in the treatment of feline hypersensitivity dermatitis is not influenced by the feeding status. Vet Dermatol. 2012;23(suppl. 1):64–5. (abstract) 37. Koch SN, Torres SMF, Diaz S, et al. Subcutaneous administration of ciclosporin in 11 allergic cats – a pilot open-label uncontrolled clinical trial. Vet Dermatol. 2018;29:107–e43. 38. Heinrich NA, McKeever PJ, Eisenschenk MC. Adverse events in 50 cats with allergic dermatitis receiving ciclosporin. Vet Dermatol. 2011;22:511–20. 39. Last RD, Suzuki Y, Manning T. A case of fatal systemic toxoplasmosis in a cat being treated with cyclosporin a for feline atopy. Vet Dermatol. 2004;15:194–8. 40. Scott DW, Miller WH Jr. Antihistamines in the management of allergic pruritus in dogs and cats. J Small Anim Pract. 1999;40:359–64. 41. Papich MG, Schooley EK, Reinero CR. Pharmacokinetics of cetirizine in healthy cats. Am J Vet Res. 2008;69:670–4. 42. Griffin JS, Scott DW, Miller WH Jr, et al. An open clinical trial on the efficacy of cetirizine hydrochloride in the management of allergic pruritus in cats. Can Vet J. 2012;53:47–50. 43. Wildermuth K, Zabel S, Rosychuk RA. The efficacy of cetirizine hydrochloride on the pruritus of cats with atopic dermatitis: a randomized, double-blind, placebo-controlled, crossover study. Vet Dermatol. 2013;24:576–681, e137-8. 44. Ortalda C, Noli C, Colombo S, Borio S. Oclacitinib in feline nonflea-, nonfood-induced hypersensitivity dermatitis: results of a small prospective pilot study of client-owned cats. Vet Dermatol. 2015;26:235–e52. 45. Lopes NL, Campos DR, Machado MA, Alves MSR, de Souza MSG, da Veiga CCP, Merlo A, Scott FB, Fernandes JI. A blinded, randomized, placebo-controlled trial of the safety of oclacitinib in cats. BMC Vet Res. 2019;15(1):137. 46. Scarampella F, Abramo F, Noli C. Clinical and histological evaluation of an analogue of palmitoylethanolamide, PLR 120 (comicronized Palmidrol INN) in cats with eosinophilic granuloma and eosinophilic plaque: a pilot study. Vet Dermatol. 2001 Feb;12(1):29–39. 47. Noli C, Della Valle MF, Miolo A, Medori C, Schievano C; Skinalia Clinical Research Group. Effect of dietary supplementation with ultramicronized palmitoylethanolamide in maintaining remission in cats with nonflea hypersensitivity dermatitis: a double-blind, multicentre, randomized, placebo-controlled study.Vet Dermatol. 2019;30:387–e117. 48. Maina E, Fontaine J. Use of maropitant for the control of pruritus in non-flea, non-foodinduced feline hypersensitivity dermatitis: an open label uncontrolled pilot study. J Feline Med Surg. 2019;21:967–72. 49. Harvey RG. Management of feline miliary dermatitis by supplementing the diet with essential fatty acids. Vet Rec. 1991;128:326–9. 50. Harvey RG. The effect of varying proportions of evening primrose oil and fish oil on cats with crusting dermatosis (miliary dermatitis). Vet Rec. 1993a;133:208–11. 51. Harvey RG. A comparison of evening primrose oil and sunflower oil for the management of papulocrustous dermatitis in cats. Vet Rec. 1993b;133:571–3. 52. Miller WH, Scott DW, Wellington JR. Efficacy of DVM Derm caps liquid in the management of allergic and inflammatory dermatoses of the cat. JAAHA. 1993;29:37–40. VetBooks.ir Mosquito-byte Hypersensitivity Ken Mason Abstract Feline mosquito bite allergy has a worldwide distribution occurring where cats are seasonally exposed to mosquitoes. The distinctive skin lesions are punctate ulcers, crusts and pigmentary changes on the face, ears and nose. Associated pruritus causes face and nose pawing resulting in bleeding. Foot pad hyperkeratosis, crusts and pigmentary changes occur in some cats. Confining the cat inside a screened area and in late afternoon reduces severity of signs; intermittent corticosteroid with confinement also helps. Newer repellent pyrethroid/pyrethrins safe for cats are becoming available and prove useful to affected cats. Introduction Feline mosquito bite hypersensitivity is an uncommon, seasonal, visually distinctive pruritic dermatitis typically affecting the face, ears and footpads [1–4]. The disease was originally described in 1984 by Wilkinson and Bate as a seasonal variant of the eosinophilic granuloma complex that improved on hospitalization [5]. In 1991, Mason and Evans hypothesized that the cause was a mosquito bite hypersensitivity, when they realized that lesions were restricted to short-haired or non-haired areas, such as the nose and footpads [1]. The authors demonstrated that clipping the hair short on the forehead resulted in lesions, when the cat was K. Mason (*) Specialist Veterinary Dermatologist, Animal Allergy & Dermatology Service, Slacks Creek, QLD, Australia e-mail: ken@dermcare.com.au © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_24 489 VetBooks.ir 490 K. Mason Fig. 1 At examination the cat presented with crusted ulceration on ear tips, erythema, crusts and depigmentation of the nasal bridge and paw and small punctate ulcers and depigmentation of the nasal planum Fig. 2 After 1 week of hospitalization, the cat presents improvement of lesions. The forehead coat was clipped before returning to home environment to prove that areas with short coat are predisposed to lesions exposed to the home environment. Only some cats in a multi-cat household developed lesions, further supporting an environmental hypersensitivity cause. The final proof that mosquito bite caused the skin disease is demonstrated in the sequence of photos in Figs. 1, 2, 3 and 4. Pathogenesis and Epidemiology Similarly to flea allergy dermatitis (FAD), mosquito bite allergy is an IgE-mediated type I (immediate) hypersensitivity reaction [1, 2, 4]. The disease is seasonal, occurring intermittently in the spring and continuing through summer, waning in autumn and usually absent in winter. In subsequent years, the allergy and lesion severity may increase depending on weather pattern, favouring or not mosquito breeding. There is no age or sex predilection; usually affected cats are adult and have been VetBooks.ir Mosquito-byte Hypersensitivity 491 Fig. 3 Re-examination after 1 week at home environment: clipped areas present new lesions and previously improved lesions have flared up. The cat was then returned home and kept in a mosquito netting-covered cage outside Fig. 4 When living at home in an outside environment in a mosquito proof netting-enclosed cage, lesions improved again. After a hole cut in the net, mosquitoes could enter and bite the cat again exposed to more than one mosquito season. Occurrence is more commonly reported in cats that venture outside in geographic regions where mosquitoes are endemic. In multi-cat households, only one or a few cats are affected. The disease occurs anywhere cats are exposed to mosquitoes. Clinical Signs The striking and typical clinical manifestations of mosquito bite hypersensitivity are erythema, crusted and ulcerated ear margins, papules to small nodules with focal crusting on the haired ear surface, punctate ulcers to severely crusted lesions on the nasal bridge and erythema, ulceration and depigmentation of the nasal planum (Figs. 1 and 5). On the footpads, there may be hyperkeratosis often affecting the margins and variable pigmentation alteration. Pruritus can be intense during active mosquito challenge, leading to self-trauma and bleeding. VetBooks.ir 492 K. Mason Fig. 5 After the mosquitoes bit the nose, the skin redeveloped inflammation, and skin biopsies were sampled again; sutures are visible Fig. 6 Eosinophilic ulcer (indolent ulcer) eroding upper lip due to mosquito bite hypersensitivity There are a variety of other less typical lesions, especially in cats living in severely mosquito-infested areas like swamps and irrigation areas, such as eosinophilic plaques, indolent lip ulcers (Fig. 6), hairless chin nodules and linear granulomas on the body. Eosinophilic keratoconjunctivitis is occasionally present and waxes and wanes with mosquito challenge. Regional lymph nodes, particularly the submandibular ones, may be enlarged and the temperature may be slightly raised. Differential Diagnoses and Diagnostic Tests The clinical features are sufficiently characteristic to make the diagnosis in typical cases; however there are potential alternative diagnoses such as squamous cell carcinoma and herpesvirus (FeHV-1) dermatitis, so that confirmation tests may be needed. Herpesvirus dermatitis can present with large crusts on the nasal bridge, and in squamous cell carcinoma, erosive, crusted lesions on the ear tip and nose may VetBooks.ir Mosquito-byte Hypersensitivity 493 Fig. 7 Photomicrograph histopathology section H&E stain showing follicular necrosis (arrow) and dermal inflammation of eosinophils and macrophages (star) develop, particularly in white skin. Footpad hyperkeratosis can present a diagnostic dilemma, given the difficulty of making a diagnosis when confronted with discrete pad keratoses. In case of lesions of the eosinophilic granuloma complex, other allergic causes should be considered. Intradermal skin test and blood immunoassay may be supportive if mosquito antigen is available. Blood haematology may show a raised eosinophil count. Similarly, cytology of lesions and lymph nodes can be supportive if dominated by eosinophils and may help to rule out alternative diseases, such as squamous cell carcinoma. The diagnosis may be confirmed if isolation in a hospital or mosquito-free home or enclosure results in resolution of acute signs within days and when return to home outside causes a relapse of pruritus and lesions. Histopathological examination of lesions is classically characterized by eosinophilic follicular necrosis. Common findings are eosinophilic folliculitis and furunculosis, surface serocellular crusts, hyperplastic spongiotic epidermis with eosinophil exocytosis and micro-pustules and a diffuse dermal eosinophilic inflammation, with a few lymphocytes and occasional flame figures (Fig. 7). Treatment Avoidance of mosquitoes as much as possible is the mainstay of treatment. Affected cats should be kept indoors behind insect screened enclosures, where mosquito exposure is prevented. Insect repellents designed for dogs or humans are toxic to cats [6]. However, natural pyrethrin from the chrysanthemum flowers and the newer synthetic flumethrin are safe for cats and could help to manage mosquito bite allergic patients. Very few products are approved for this disease in cats, but some, such as collars, have proven repellent activity against sandfly vectors of leishmaniosis [7–9]. Supplementary anti-pruritic glucocorticoids help in case of disease flares. VetBooks.ir 494 K. Mason Yard environmental mosquito control may be helpful and is an important preventative human health consideration. Standing water should be eliminated to decrease mosquito breeding grounds. Conclusion The typical presentation of mosquito bite allergy is sufficiently distinctive to make a diagnosis without supportive tests. However, the less typical forms and footpad hyperkeratosis present a diagnostic challenge, and the aetiology can be overlooked, leading to chronic high doses of corticosteroids and subsequent major adverse effects. Keeping the cat inside in the late afternoon and overnight and flumethrin collars are likely to be beneficial. References 1. Mason KV, Evans AG. Mosquito bite-caused eosinophilic dermatitis in cats. J Am Vet Med Assoc. 1991;198(12):2086–8. 2. Nagata M, Ishida T. Cutaneous reactivity to mosquito bites and its antigens in cats. Vet Dermatol. 1997;8(1):19–26. 3. Johnstone AC, Graham DG, Andersen HJ. A seasonal eosinophilic dermatitis in cats. N Z Vet J. 1992;40(4):168–72. 4. Ihrke PJ, Gross TL. Conference in dermatology—no. 2 mosquito-bite hypersensitivity in a cat. Vet Dermatol. 1994;5(1):33–6. 5. Wilkinson GT, Bate MJ. A possible further clinical manifestation of the feline eosinophilic granuloma complex. J Am Anim Hosp Assoc. 1984;20:325–31. 6. Dymond NL, Swift IM. Permethrin toxicity in cats: a retrospective study of 20 cases. Aust Vet J. 2008;86(6):219–23. 7. Stanneck D, Kruedewagen EM, Fourie JJ, Horak IG, Davis W, Krieger KJ. Efficacy of an imidacloprid/flumethrin collar against fleas and ticks on cats. Parasit Vectors. 2012;5:82. 8. Stanneck D, Rass J, Radeloff I, Kruedewagen E, Le Sueur C, Hellmann K, Krieger K. Evaluation of the long-term efficacy and safety of an imidacloprid 10% / flumethrin 4.5% polymer matrix collar (Seresto (R)) in dogs and cats naturally infested with fleas and/or ticks in multicentre clinical field studies in Europe. Parasit Vectors. 2012;5:66. 9. Brianti E, Falsone L, Napoli E, et al. Prevention of feline leishmaniosis with an imidacloprid 10%/flumethrin 4.5% polymer matrix collar. Parasit Vectors. 2017;10:334. VetBooks.ir Autoimmune Diseases Petra Bizikova Abstract Autoimmune skin diseases (AISDs) in cats are very rare and account for less than 2% of all skin diseases for which cats are seen by dermatologists. The most common AISD seen in this species is pemphigus foliaceus, for which numerous case reports and case series can be found in the literature. In contrast, other AISDs are very rare and limited to only few case reports published in the peer- reviewed literature over the last two decades. Many of these diseases are clinically and histologically homologous to diseases described in people and dogs, and, although the pathomechanism of these feline counterparts is unknown, similar mechanisms leading to the disruption of the epidermal cohesion or destruction of skin adnexae are hypothesized. Such mechanisms involve autoantibodies in diseases like pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigus, and autoimmune subepidermal blistering diseases, or autoreactive T cells in diseases like paraneoplastic pemphigus, cutaneous lupus, and vitiligo. This chapter will provide an overview of the current knowledge about feline AISDs available in the published literature. Introduction A healthy immune system protects the body from an onslaught of invading pathogens as well as from its own damaged or potentially neoplastic cells on a daily basis. Under specific circumstances (genetics, environment, infection, etc.), however, the same immune system may get awry and start targeting self-antigens. This break of P. Bizikova (*) North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA e-mail: pbiziko@ncsu.edu © Springer Nature Switzerland AG 2020 C. Noli, S. Colombo (eds.), Feline Dermatology, https://doi.org/10.1007/978-3-030-29836-4_25 495 VetBooks.ir 496 P. Bizikova a self-tolerance results in an injury to the body, which at the turn of the twentieth century was named a horror autotoxicus by Paul Ehrlich. Such autoimmune attack can be caused by autoantibodies (e.g., pemphigus) or by autoreactive T lymphocytes (e.g., cutaneous lupus). Autoimmune skin diseases (AISDs) are rare in cats and account for less than 2% of all skin diseases for which cats are seen by a dermatologist [1]. The most common AISD seen in this species is pemphigus foliaceus, for which numerous case reports and case series can be found in the literature. In contrast, other AISDs are very rare and limited to only few case reports published in the peer-reviewed literature over the last two decades. Due to the rarity of AISDs in cats, information about the identity of the autoantigen and the disease pathogenesis remains unknown. utoimmune Skin Diseases Affecting the Epidermal A and Dermo-Epidermal Adhesion An intact skin is a critically important organ that functions as a first-line defense mechanism against physical and chemical damage. Its integrity is dependent on complex structures maintaining cell-cell and cell-matrix adhesions [2, 3]. Several AISDs disrupting this cohesion have been recognized in cats. The mechanism by which this adhesion is disrupted varies depending on the type of disease. (a) Disruption of keratinocyte adhesion – intra-epidermal blister formation due to desmosome dissociation (pemphigus foliaceus (PF), pemphigus vulgaris (PV), paraneoplastic pemphigus (PNP)) (b) Disruption of basement membrane adhesion – subepidermal blister formation due to dermo-epidermal separation (bullous pemphigoid (BP), mucous membrane pemphigoid (MMP)) Desmosome Autoimmunity emphigus Foliaceus (PF) P Pemphigus foliaceus is the most common autoimmune skin disease in cats that accounts for about 1% of all skin diseases for which cats are seen by dermatologists [1]. Although the pathogenesis of feline PF has not been studied in such extent as it has been in dogs, it is believed that, like in dogs and people, antikeratinocyte IgG autoantibodies disrupt desmosomal adhesion between keratinocytes and induce subcorneal blisters in a form of pustules (Fig. 1a). Indeed, tissue-bound and circulating antikeratinocyte IgG have been detected in the majority of cats with PF (Fig. 2d) [4, 5]. The major target autoantigen that in people and dogs is desmoglein-1 and desmocollin-1, respectively, remains unknown for feline PF. Signalment Cats of different breeds have been reported to suffer with PF, but a breed predisposition has not been confirmed yet. The most commonly reported breeds Autoimmune Diseases 497 b VetBooks.ir a c e d f Fig. 1 Feline pemphigus foliaceus – clinical lesions: (a) Pustule and scale-crust; (b) well- demarcated scale-crust suggesting a pustular origin on the concave pinna; (c) claw skin fold with erythema, superficial erosions, scale-crust, and purulent exudate; (d) erosions and scale-crust on the nasal planum and dorsal muzzle; (e) scale-crust around the areola; (f) erosions and scale-crust on the footpad. (photo f – courtesy of Dr. Andrea Lamm) 498 P. Bizikova b c d PF cat: Serum anti-keratinocyte IgG Healthy cat: Serum anti-keratinocyte IgG VetBooks.ir a Fig. 2 Feline pemphigus foliaceus – histopathology and indirect immunofluorescence: (a) Subcorneal pustule with acantholytic keratinocytes; (b) close-up of individualized and clustered acantholytic keratinocytes (Courtesy of Dr. Keith Linder); (c) and (d) indirect immunofluorescence using healthy feline serum (c) and serum from a cat with pemphigus foliaceus (d). Note the intercellular, web-like immunofluorescence pattern in the PF-affected cat sample (d) caused by circulating anti-keratinocyte IgG antibodies include domestic shorthaired, Siamese, Persian and Persian-crossbred, Burmese, Himalayan, and domestic medium-haired cats [6]. Pemphigus foliaceus affects usually adult cats (median age of onset about 6 years), though the range varies greatly (0.25–16 years) [4, 6–9]. A sex predilection has not been confirmed, but females appear to be marginally over-represented according to a recent review [6]. In most cats, a specific trigger precipitating the PF onset cannot be identified. Rare reports of a drug-triggered PF and PF associated with a thymoma can be found in the literature [8, 10–16]. Clinical Signs The primary skin lesion of feline PF is a subcorneal pustule, which, because of its superficial nature, progresses rapidly into an erosion and crust. Indeed, the two latter skin lesions may represent the only clinical findings during the physical examination. Lesions are usually bilaterally symmetric with pinnae and claw skin folds being the most commonly affected body areas (Fig. 1b and c) [6]. Claw skin folds often exhibit accumulation of a thick purulent exudate, which is usually related to secondary bacterial infections seen in this body region more often than in others [17]. Other typically affected body areas include nasal planum, eyelids, pawpads, VetBooks.ir Autoimmune Diseases 499 and periareolar areas (Fig. 1 d, e). Typical pawpads lesions are scaling, crusting, and hyperkeratosis, though they are usually not as prominent as in dogs (Fig. 1f). Pustules, if found, can be seen at the periphery of the pawpads not in contact with the ground. Most cats (81%) exhibit lesions on two or more body regions, while lesions localized to a single body area are less common (19%). More than a half of cats are pruritic and show systemic signs such as lethargy, fever, and/or anorexia. Diagnostic Approach The most critical and often challenging step in the diagnostic approach is the identification of a subcorneal pustular process. Indeed, while there are several erosive skin diseases in cats, the list of diseases presenting with primary subcorneal pustules with acantholysis is limited to PF and to anecdotal reports of pustular dermatophytosis; the latter has been reported to exhibit minimal to no acantholysis [18]. Bullous impetigo, a subcorneal pustular dermatitis with variable degree of acantholysis caused by Staphylococcus aureus and pseudintermedius in people and dogs, has not been described in cats yet [19, 20]. Lesions suggestive of a subcorneal pustular dermatitis include intact pustules, sharply demarcated, pinpoint to few millimeters large; superficial erosions; or scaling and crusting (Fig. 1a, b). The acantholytic nature of the disease can be confirmed by cytology taken from an intact pustule, from the underneath of a crust with an active erosion and exudation, or from the caseous pus around nails and/or by a biopsy of similar lesions. It is important to include crusts in the biopsy sample. Microscopic examination of biopsy samples reveals acantholytic keratinocytes, usually numerous, within a neutrophilic or mixed neutrophilic and eosinophilic, subcorneal or intragranular pustule (Fig. 2a, b). Ghost acantholytic cells can be found within the crusts, and, in many cases, may be the only histological evidence of the disease process. Aerobic bacterial culture should be considered in cases in which infection cannot be clinically ruled out, and fungal culture and special stains should be considered in cases in which dermatophytosis is suspected, particularly if a pustular folliculitis, lymphocytic mural folliculitis, and/or prominent hyperkeratosis is present in biopsy samples. An immunological testing for antikeratinocyte autoantibodies by direct or indirect immunofluorescence is not commercially available, nor the sensitivity and, particularly, specificity of such tests is known. Therefore, the current diagnosis of PF is based on the combination of (i) skin lesion character and distribution, (ii) exclusion of an infection, and (iii) supportive cytology and/or histopathology confirming acantholytic pustular dermatitis [21]. Treatment Cats with PF have usually positive response to treatment, and the majority of them (93%) reach disease control (cessation of active lesions and healing of original lesions) within a few weeks (median time, 3 weeks) [6]. In most cats, the disease control can be achieved by a glucocorticoid monotherapy (e.g., prednisolone, 2–4 mg/ kg/day; triamcinolone aceponate, 0.2–0.6 mg/kg/day; dexamethasone, 0.1–0.2 mg/ kg/day). The dosage reduction is recommended only once the disease has been inactive for at least 2 weeks and most original skin lesions have healed (20–25% dosage VetBooks.ir 500 P. Bizikova reduction every 2–4 weeks, though faster reduction is possible). The use of nonsteroidal agents is implemented in cats: (i) in which disease control is not achieved within 4 weeks using appropriate glucocorticoid dosages, (ii) exhibiting severe adverse effects related to glucocorticoids, or (iii) in which the dosage of glucocorticoids cannot be significantly reduced. Non-steroidal drugs reported to induce disease control in cats include ciclosporin (5–10 mg/kg/day), chlorambucil (0.1–0.3 mg/kg/ day), azathioprine (1.1 mg/kg every other day) [7], and aurothioglucose (0.5 mg/ kg/week). The two latter are not used commonly either because of the high risk of a bone marrow suppression (azathioprine) or its unavailability on the market (aurothioglucose). The risk of side effects in azathioprine-treated cats is dose-dependent, and, anecdotally, lower dosages (e.g., 0.3 mg/kg every other day) have been reported to be successful in managing other immune-mediated diseases [22]. According to the literature review, only a minority of cats (15%) appears to achieve a long-term disease remission off drugs [6]. Most cats require a long-term medical management with glucocorticoids or non-steroidal drugs such as ciclosporin or chlorambucil. The median maintenance dosages are usually lower than those required for the induction of the disease control (e.g., prednisolone, 0.5 mg/kg/day; dexamethasone, 0.03 mg/kg/day; or ciclosporin, 5 mg/kg/day). A combination of doxycycline and niacinamide has also been reported to be an effective maintenance therapy in cats with PF [17]. In refractory cases, other immunosuppressants (e.g., mycophenolate, leflunomide) could be considered, though the evidence of efficacy of these drugs in feline PF is currently lacking. Box 1: Feline PF Treatment Outline Using Similar Principles than Those Used in Human Pemphigus [42] (I) Induce rapid disease control (i.e., time at which new lesions cease to form and old lesions start to heal) First line treatment: prednisolone or methylprednisolone 2–4 mg/kg/ day (or its equivalent; e.g., triamcinolone aceponate, dexamethasone) until disease control is reached. (II) Start gradual glucocorticoid dosage reduction (25% every 2 weeks) once the end of consolidation phase is reached (i.e., time at which no new lesions have developed for at least 2 weeks and approximately 80% of original lesions have healed). Consider also to taper to every-other- day administration before reducing the daily dose. (III) Continue with the gradual glucocorticoid dosage reduction until the lowest effective dosage is identified or the cat is able to remain in remission off of drugs (a long-term remission off drugs has been reported in about 15% of cats). III.a.Consider topical glucocorticoids (e.g., hydrocortisone aceponate) or tacrolimus to control minor, localized flares. III.b.In case of a more severe flare-up, increase the dose of glucocorticoids back to the second to the last effective dosage. If the flare-up VetBooks.ir Autoimmune Diseases 501 cannot be controlled within 2 weeks, increase the glucocorticoid dosage back to the initial immunosuppressive dosage. (IV) Add non-steroidal immunosuppressive drug∗ if: IV.a.The dosage of glucocorticoid cannot be reduced enough to limit the risk of side effects associated with a long-term glucocorticoid treatment. IV.b. The patient suffers with intolerable side effects caused by glucocorticoids. IV.c.Disease control cannot be achieved with glucocorticoid monotherapy within 4–6 weeks. * Frequently selected non-steroidal immunosuppressive drugs in cats with PF are ciclosporin (5–10 mg/kg/day) or chlorambucil (0.2 mg/kg/every other day). (V) V. Maintenance treatment: V.a.Maintain the disease with the lowest possible dosage of drug(s); attempt to reduce the dosage of glucocorticoids as much as possible, or to complete replace them with a non-steroidal immunosuppressant. V.b.Monitor for side effects (usually complete blood count, chemistry panel, urinalysis, and urine culture every 6–12 months, though the frequency and type of tests depends on the used drug(s), age of the cat, and its general health status). V.c.Avoid potential flare-up triggers (e.g., UV light, etc.). Pemphigus Vulgaris (PV) In contrast to people, PV is considered to check if this should autoimmune dermatoses in animals, including the cat [4]. Because of the small number of described cases, breed, age, and sex predilections cannot be reliably estimated in cats. The clinical and histological homology between feline, canine, and human PV suggests similar pathomechanism; however, while desmoglein-3 has been confirmed to be the major target autoantigen in human and canine PV, the major target antigen in feline PV remains unknown. Clinical Signs Similarly to people, the primary lesion of animal PV is a flaccid vesicle rapidly progressing to a deep erosion (Fig. 3a–c). Erosions are seen more often due to the fragile nature of the vesicles, and further epithelial splitting beyond the preexisting erosion, even extending to a great distance (marginal Nikolsky’s signs), can be elicited by pulling on the blister remnant. Crusts can develop over lesions at the mucocutaneous junctions or haired skin. The current knowledge about the lesion distribution in cats is extracted from less than a handful of described cases in the literature and from anecdotal reports [4, 23]. Like in people and dogs, lesions frequently involve the oral cavity, especially gums and hard palate, lips, nasal planum, P. Bizikova VetBooks.ir 502 Fig. 3 Pemphigus vulgaris: Cats with pemphigus vulgaris with deep erosions affecting the (a) oral cavity, lips, and nasal philtrum; (b) periocular region; and (c) pawpads. A histopathology of feline pemphigus vulgaris showing the classic suprabasilar acantholysis (d). (Courtesy of Dr. Karen Trainor) and philtrum (Fig. 3a, b). Haired skin involvement, as described in people, dogs, and horses [20, 24], and pawpad involvement (Fig. 3c) have been observed as well. Sialorrhea, halitosis, dysphagia, lethargy, and enlarged submandibular lymph nodes are common. Diagnostic Approach Because intact vesicles are rarely found, primary erosive diseases, especially those affecting oral cavity and mucocutaneous junctions, present the major differential diagnoses for feline PV. These include common diseases such as viral stomatitis caused by herpesvirus or calicivirus and chronic ulcerative stomatitis or rare diseases such as autoimmune subepidermal blistering skin diseases. The diagnosis of PV is confirmed by a biopsy, which shows suprabasilar acantholysis with basal cells remaining attached to the basement membrane (Fig. 3d). Samples for histopathology should be collected from the margin of the blister or erosion and should include VetBooks.ir Autoimmune Diseases 503 affected as well as intact tissue adjacent to the blister or erosion. The diagnostic value of direct and indirect immunofluorescence for antikeratinocyte autoantibodies has not been addressed in cats, and, so far, only tissue-bound, but not circulating, antikeratinocyte antibodies have been uncovered in cats with PV [4, 23]. Treatment The information about the treatment and outcome of feline PV is very limited. Oral glucocorticoids (4–6 mg/kg/day of prednisolone) were reported to induc

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